We are searching data for your request:
Upon completion, a link will appear to access the found materials.
During beta selection, a candidate T cell tries to use its pre-TCR to bind to cTECs in the thymus. If tonic signaling occurs between the pre-TCR and the cTEC MHC, then it will progress through later stages of T-cell development.
If the pre-TCR needs to be antigen-specific, then the only cells passing through beta-selection will be those with affinity for thymic proteins, which seems like a problem. Is beta-selection actually antigen-dependent?
Positive and Negative Selection of T Cells
Adaptive immune cells, like T cells, play a critical role in protecting our bodies against invading pathogens, a task that relies upon their ability to recognize pathogens as foreign, or ‘non-self’. This begs the question, though, of how adaptive immune cells distinguish between self and non-self. How is it that T cells know to attack and kill an invading bacterial cell while leaving our neighboring self-cells alone and unharmed? That answer to this question lies in the processes of positive and negative selection.
Early thymocyte development
The most efficient T cell progenitor populations in the thymus have multilineage potential, indicating that they are derived from multipotent precursors in the bone marrow, but the identity of the precursors that migrate to the thymus has remained elusive. Marieke Lavaert (Ghent University) used single-cell transcriptional profiling of human CD34 + thymocytes to characterize early T cell lineage commitment 2 . Integration of these findings with datasets interrogating CD34 + progenitors in the bone marrow and peripheral blood identified two putative thymic-seeding progenitors, suggesting two parallel developmental pathways. Assessment of developmental potential in silico and ex vivo established that both candidate T cell progenitors were capable of producing T cells, but one also possessed significant plasmacytoid DC potential. The results provided new insight into what have so far been relatively poorly characterized populations in humans. As thymocytes progress from the multipotent early T cell precursor (ETP) stage, they lose non-T cell lineage potential and commit to the T cell fate. Boyoung Shin (California Institute of Technology) probed the roles of the transcription factors RUNX1 and RUNX3 during fate commitment in mice 3 . Unlike in mature T cells, RUNX1 and RUNX3 were found to act redundantly in early T cell precursors. Despite stable expression, Runx factors preferentially regulate dynamically changing genes essential for commitment by switching their genome-wide binding and interactions with cofactors.
Chapter 8 Questions Immunology .
T cells entering the thymus have no Ag receptors and no lineage commitment while T cells leaving the thymus are functional, mature T cells with TCR that are tolerant to self and restricted to self-MHC.
early thymocyte development
- commitment of hemipoietic precursors to T cell lineage
- Ag receptor gene rearrangement initiation
- Beta selection where DNA thymocytes that have rearranged TCR beta chains are identified and expanded
drives T cell commitment. When it is knocked out in HSC, the B cells develop in the thymus. When it is overexpressed in HSC, T cells develop in the bone marrow.
what initiates thymocyte development process
it begins when a TSP migrates from the bone marrow to the thymus through blood vessels at the corticomedullary boundary via chemokine receptors.
- early T cells lacking CD4 and CD8
- four subsets DN1-DN4 based on presence or absence of cell surface molecules: cKit, CD44, CD25
TSPs receive Notch signals upon entering the thymus and begin restricting themselves to the T cell lineage. Then they travel to the cortex to gain expression of CD25 to become a DN-2 thymocyte
Thymocytes in the cortex begin TCR gene rearrangements of the gamma, delta, and beta chains. The alpha chain locus is unavailable to recombinase at this time. Expression of CD44 and cKit is reduced and the T cell precursor becomes fully committed to the T cell lineage.
preTCR is expressed in the cortex and lineage commitment occurs between either TCR-gamma-delta or TCR-alpha-beta. If the beta chain was successfully arranged in the DN-2 stage, then TCR-alpha-beta lineage will be chosen. This stage also includes pre-TCR signaling and beta selection.
results in commitment to the TCR-alpha-beta lineage, another round of proliferation, maturation to DP stage, and initiation of TCR-alpha chain rearrangements, allelic exclusion
detects thymocytes that successfully rearranged the TCR beta chain. intiated by assembly of TCR beta protein with pre-Talpha chain and CD3 complex to form pre-TCR
This is the pre-DP stage and it occurs in the cortex. Beta selection stops additional TCR beta chains from being rearranged (Exclusion of B locus), stimulates proliferation of selected beta chains, stimulates expression of CD4 and CD8 coreceptors and begins TCR alpha chain locus rearrangement to produce a DP thymocyte w/ mature TCR
prevalent type present after birth and exit the thymus as single positive cells. only requires rearrangement of B receptor gene for commitment. high receptor diversity. can only secrete cytokines after Ag encounter in secondary lymphoid tissues
prevalent type before birth and exits the thymus as DN cell. must generate two fxnal proteins that depend on 2 separate rearrangement events. low receptor diversity. atypical Ag/MHC such as lipids. important in mucosal immunity. emerge from the thymus able to secrete cytokines.
TCR recognizes peptide antigens only when combined with self-MHC molecules
T cells have to recognize self MHC with some affinity but cannot initiate a response to self-MHC/self-peptides
function of thymic selection
screen the large population of of newly generated DP thymocytes for the few cells whose TCRs exhibit both self tolerance and self-restriction.
affinity model of selection
DP thymocytes whos abTCR's do not bind with MHC with the right affinity die from neglect in the cortex. Those ab TCRs that do bind with high affinity are clonally deleted (negative selection). DP thymocytes whose receptors bind with intermediate to low affinity to ubiquitous MHCs/self peptides on cTECs are positively selected and mature to SP T lymphocytes (CD4+ or CD8+) in the medulla
what happens after positive selection in the thymus?
The CD4+ or CD8+ T lymphocytes migrate to the medulla where they are mTEC that exhibits negative selection and expresses tissue specific antigens secondary to a transcription factor AIRE
lineage commitment of T cells
results in silencing of one coreceptor gene (CD4 or CD8) and expression of genes associated with a specific lineage. several different models have been proposed to describe the mechanisms responsible for lineage commitment-reach, teach, strength
Kyewski, B. & Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571–606 (2006).
Nakagawa, Y. et al. Thymic nurse cells provide microenvironment for secondary T cell receptor-α rearrangement in cortical thymocytes. Proc. Natl Acad. Sci. USA 109, 20572–20577 (2012).
Klein, L., Hinterberger, M., Wirnsberger, G. & Kyewski, B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nature Rev. Immunol. 9, 833–844 (2009).
Florea, B. I. et al. Activity-based profiling reveals reactivity of the murine thymoproteasome-specific subunit β5t. Chem. Biol. 17, 795–801 (2010).
Murata, S. et al. Regulation of CD8 + T cell development by thymus-specific proteasomes. Science 316, 1349–1353 (2007).
Nakagawa, T. et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450–453 (1998).
Gommeaux, J. et al. Thymus-specific serine protease regulates positive selection of a subset of CD4 + thymocytes. Eur. J. Immunol. 39, 956–964 (2009).
Nedjic, J., Aichinger, M., Mizushima, N. & Klein, L. Macroautophagy, endogenous MHC II loading and T cell selection: the benefits of breaking the rules. Curr. Opin. Immunol. 21, 92–97 (2009).
Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N. & Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396–400 (2008).
Honey, K., Nakagawa, T., Peters, C. & Rudensky, A. Cathepsin L regulates CD4 + T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med. 195, 1349–1358 (2002).
Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8 + T cells. Immunity 32, 29–40 (2010).
Xing, Y., Jameson, S. C. & Hogquist, K. A. Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection. Proc. Natl Acad. Sci. USA 110, 6979–6984 (2013).
Ziegler, A., Muller, C. A., Bockmann, R. A. & Uchanska-Ziegler, B. Low-affinity peptides and T-cell selection. Trends Immunol. 30, 53–60 (2009).
Ryan, K. R., McNeil, L. K., Dao, C., Jensen, P. E. & Evavold, B. D. Modification of peptide interaction with MHC creates TCR partial agonists. Cell. Immunol. 227, 70–78 (2004).
Azzam, H. S. et al. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188, 2301–2311 (1998).
Stefanova, I., Dorfman, J. R. & Germain, R. N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429–434 (2002).
Cho, J. H., Kim, H. O., Surh, C. D. & Sprent, J. T cell receptor-dependent regulation of lipid rafts controls naive CD8 + T cell homeostasis. Immunity 32, 214–226 (2010).
Palmer, M. J., Mahajan, V. S., Chen, J., Irvine, D. J. & Lauffenburger, D. A. Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naive CD8 + T cells. Immunol. Cell Biol. 89, 581–594 (2011).
Mandl, J. N., Monteiro, J. P., Vrisekoop, N. & Germain, R. N. T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity 38, 263–274 (2013). References 18 and 19 show that T cell responsiveness is set in the thymus and maintained in mature T cells in proportion to the avidity of the positively selecting interaction. Reference 18 concludes that T cells with stronger affinity for self dominate in response to infections, whereas reference 19 challenges the generality of such correlations.
Persaud, S. P., Parker, C. R., Lo, W. L., Weber, K. S. & Allen, P. M. Intrinsic CD4 + T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC. Nature Immunol. 15, 266–274 (2014).
Surh, C. D. & Sprent, J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372, 100–103 (1994).
Daley, S. R., Hu, D. Y. & Goodnow, C. C. Helios marks strongly autoreactive CD4 + T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB. J. Exp. Med. 210, 269–285 (2013).
Stritesky, G. L. et al. Murine thymic selection quantified using a unique method to capture deleted T cells. Proc. Natl Acad. Sci. USA 110, 4679–4684 (2013). Using different approaches, references 22 and 23 quantify 'early' and 'late' negative selection in the cortex and the medulla, respectively, and conclude that the extent of clonal deletion in the cortex exceeds that in the medulla.
McCaughtry, T. M., Baldwin, T. A., Wilken, M. S. & Hogquist, K. A. Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla. J. Exp. Med. 205, 2575–2584 (2008).
Melichar, H. J., Ross, J. O., Herzmark, P., Hogquist, K. A. & Robey, E. A. Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci. Signal. 6, ra92 (2013).
Irla, M., Hollander, G. & Reith, W. Control of central self-tolerance induction by autoreactive CD4 + thymocytes. Trends Immunol. 31, 71–79 (2010).
Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).
Peterson, P., Org, T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nature Rev. Immunol. 8, 948–957 (2008).
Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004).
Oukka, M., Cohen-Tannoudji, M., Tanaka, Y., Babinet, C. & Kosmatopoulos, K. Medullary thymic epithelial cells induce tolerance to intracellular proteins. J. Immunol. 156, 968–975 (1996).
Hinterberger, M. et al. Autonomous role of medullary thymic epithelial cells in central CD4 + T cell tolerance. Nature Immunol. 11, 512–519 (2010). Through diminution of MHC class II on mTECs, this study documents an autonomous contribution of mTECs to both dominant and recessive mechanisms of CD4 + T cell tolerance and provides experimental support for the affinity model of T Reg cell development versus clonal deletion.
Klein, L., Klein, T., Ruther, U. & Kyewski, B. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188, 5–16 (1998).
Oukka, M. et al. CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium. Immunity 4, 545–553 (1996).
Aschenbrenner, K. et al. Selection of Foxp3 + regulatory T cells specific for self antigen expressed and presented by Aire + medullary thymic epithelial cells. Nature Immunol. 8, 351–358 (2007).
Atibalentja, D. F., Byersdorfer, C. A. & Unanue, E. R. Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction. J. Immunol. 183, 7909–7918 (2009).
Klein, L., Roettinger, B. & Kyewski, B. Sampling of complementing self-antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance. Eur. J. Immunol. 31, 2476–2486 (2001).
Munz, C. Enhancing immunity through autophagy. Annu. Rev. Immunol. 27, 423–449 (2009).
Aichinger, M., Wu, C., Nedjic, J. & Klein, L. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J. Exp. Med. 210, 287–300 (2013).
Mizushima, N. Autophagy in protein and organelle turnover. Cold Spring Harb. Symp. Quant. Biol. 76, 397–402 (2011).
Dongre, A. R. et al. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31, 1485–1494 (2001).
Klein, L., Hinterberger, M., von Rohrscheidt, J. & Aichinger, M. Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol. 32, 188–193 (2011).
Koble, C. & Kyewski, B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505–1513 (2009).
Hubert, F. X. et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118, 2462–2472 (2011).
Taniguchi, R. T. et al. Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc. Natl Acad. Sci. USA 109, 7847–7852 (2012).
Irla, M. et al. Autoantigen-specific interactions with CD4 + thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451–463 (2008).
DeVoss, J. et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203, 2727–2735 (2006).
Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).
Ehrlich, L. I., Oh, D. Y., Weissman, I. L. & Lewis, R. S. Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes. Immunity 31, 986–998 (2009).
Le Borgne, M. et al. The impact of negative selection on thymocyte migration in the medulla. Nature Immunol. 10, 823–830 (2009).
Ueda, Y. et al. Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus. Nature Commun. 3, 1098 (2012).
Klein, L. Dead man walking: how thymocytes scan the medulla. Nature Immunol. 10, 809–811 (2009).
Derbinski, J., Pinto, S., Rosch, S., Hexel, K. & Kyewski, B. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc. Natl Acad. Sci. USA 105, 657–662 (2008).
Pinto, S. et al. Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc. Natl Acad. Sci. USA 110, E3497–3505 (2013).
Villasenor, J., Besse, W., Benoist, C. & Mathis, D. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc. Natl Acad. Sci. USA 105, 15854–15859 (2008).
Wu, L. & Shortman, K. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17, 304–312 (2005).
Li, J., Park, J., Foss, D. & Goldschneider, I. Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J. Exp. Med. 206, 607–622 (2009).
Joffre, O. P., Segura, E., Savina, A. & Amigorena, S. Cross-presentation by dendritic cells. Nature Rev. Immunol. 12, 557–569 (2012).
Proietto, A. I., Lahoud, M. H. & Wu, L. Distinct functional capacities of mouse thymic and splenic dendritic cell populations. Immunol. Cell Biol. 86, 700–708 (2008).
Lei, Y. et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208, 383–394 (2011).
Baba, T., Nakamoto, Y. & Mukaida, N. Crucial contribution of thymic Sirpα + conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J. Immunol. 183, 3053–3063 (2009).
Atibalentja, D. F., Murphy, K. M. & Unanue, E. R. Functional redundancy between thymic CD8α + and Sirpα + conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins. J. Immunol. 186, 1421–1431 (2011).
Baba, T., Badr Mel, S., Tomaru, U., Ishizu, A. & Mukaida, N. Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpα + dendritic cells: a murine model. PLoS ONE 7, e41154 (2012).
Reizis, B., Colonna, M., Trinchieri, G., Barrat, F. & Gilliet, M. Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? Nature Rev. Immunol. 11, 558–565 (2011).
Villadangos, J. A. & Young, L. Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29, 352–361 (2008).
Wirnsberger, G., Mair, F. & Klein, L. Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control. Proc. Natl Acad. Sci. USA 106, 10278–10283 (2009).
Hadeiba, H. et al. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36, 438–450 (2012). This study shows that endogenous pDCs take up subcutaneously injected antigen and transport it to the thymus in a CCR9-dependent manner. Upon intravenous injection, antigen-loaded pDCs delete specific thymocytes, which indicates that migratory pDCs can support central tolerance.
Hadeiba, H. et al. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nature Immunol. 9, 1253–1260 (2008).
Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nature Immunol. 7, 1092–1100 (2006).
Akashi, K., Richie, L. I., Miyamoto, T., Carr, W. H. & Weissman, I. L. B lymphopoiesis in the thymus. J. Immunol. 164, 5221–5226 (2000).
Feyerabend, T. B. et al. Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms. Immunity 30, 67–79 (2009).
Mori, S. et al. Presence of B cell progenitors in the thymus. J. Immunol. 158, 4193–4199 (1997).
Perera, J., Meng, L., Meng, F. & Huang, H. Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection. Proc. Natl Acad. Sci. USA 110, 17011–17016 (2013). Using BCR- and TCR-transgenic mice, this study shows that autoreactive thymic B cells are efficient APCs for negative selection. Thymic B cells may capture autoantigens through their BCR and present these to developing thymocytes for clonal deletion.
Frommer, F. & Waisman, A. B cells participate in thymic negative selection of murine auto-reactive CD4 + T cells. PLoS ONE 5, e15372 (2010).
Kleindienst, P., Chretien, I., Winkler, T. & Brocker, T. Functional comparison of thymic B cells and dendritic cells in vivo. Blood 95, 2610–2616 (2000).
Guerri, L. et al. Analysis of APC types involved in CD4 tolerance and regulatory T cell generation using reaggregated thymic organ cultures. J. Immunol. 190, 2102–2110 (2013).
Yuseff, M. I., Pierobon, P., Reversat, A. & Lennon-Dumenil, A. M. How B cells capture, process and present antigens: a crucial role for cell polarity. Nature Rev. Immunol. 13, 475–486 (2013).
Weiss, S. & Bogen, B. MHC class II-restricted presentation of intracellular antigen. Cell 64, 767–776 (1991).
Munthe, L. A., Corthay, A., Os, A., Zangani, M. & Bogen, B. Systemic autoimmune disease caused by autoreactive B cells that receive chronic help from Ig V region-specific T cells. J. Immunol. 175, 2391–2400 (2005).
Detanico, T., Heiser, R. A., Aviszus, K., Bonorino, C. & Wysocki, L. J. Self-tolerance checkpoints in CD4 T cells specific for a peptide derived from the B cell antigen receptor. J. Immunol. 187, 82–91 (2011).
Ebert, P. J., Jiang, S., Xie, J., Li, Q. J. & Davis, M. M. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nature Immunol. 10, 1162–1169 (2009).
Lo, W. L. et al. An endogenous peptide positively selects and augments the activation and survival of peripheral CD4 + T cells. Nature Immunol. 10, 1155–1161 (2009).
Martin, B. et al. Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells. Nature Commun. 4, 2209 (2013).
Hsieh, C. S., Lee, H. M. & Lio, C. W. Selection of regulatory T cells in the thymus. Nature Rev. Immunol. 12, 157–167 (2012).
Wirnsberger, G., Hinterberger, M. & Klein, L. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89, 45–53 (2011).
Cowan, J. E. et al. The thymic medulla is required for Foxp3 + regulatory but not conventional CD4 + thymocyte development. J. Exp. Med. 210, 675–681 (2013).
Klein, L. & Jovanovic, K. Regulatory T cell lineage commitment in the thymus. Semin. Immunol. 23, 401–409 (2011).
Mathis, D. & Benoist, C. A decade of AIRE. Nature Rev. Immunol. 7, 645–650 (2007).
Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013). This study reports that T Reg cells that were consistently found to be enriched in prostate tumours of mice recognized an unknown antigen that was also present in the healthy prostate. These cells were found to differentiate as 'natural' (that is, thymically induced) T Reg cells in an AIRE-dependent manner, which provides evidence for a link between AIRE-mediated expression of peripheral tissue antigens and the development of organ-specific T Reg cells.
Bautista, J. L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nature Immunol. 10, 610–617 (2009).
Leung, M. W., Shen, S. & Lafaille, J. J. TCR-dependent differentiation of thymic Foxp3 + cells is limited to small clonal sizes. J. Exp. Med. 206, 2121–2130 (2009).
Moran, A. E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).
St-Pierre, C. et al. Transcriptome sequencing of neonatal thymic epithelial cells. Sci. Rep. 3, 1860 (2013).
Lv, H. et al. Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest. 121, 1561–1573 (2011).
Gottumukkala, R. V. et al. Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes. Sci. Transl Med. 4, 138ra180 (2012).
Gotter, J., Brors, B., Hergenhahn, M. & Kyewski, B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199, 155–166 (2004).
Durinovic-Bello, I. et al. Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immun. 11, 188–193 (2010).
Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nature Genet. 15, 293–297 (1997).
Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genet. 15, 289–292 (1997).
Giraud, M. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934–937 (2007).
Colobran, R. et al. Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance. Hum. Mol. Genet. 20, 3415–3423 (2011).
Klein, L., Klugmann, M., Nave, K. A., Tuohy, V. K. & Kyewski, B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nature Med. 6, 56–61 (2000).
de Jong, V. M. et al. Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans. Diabetologia 56, 2651–2658 (2013).
Pinto, S. et al. Mis-initiation of intrathymic MART-1 transcription and biased TCR usage explain the high frequency of MART-1-specific T cells. Eur. J. Immunol. (in the press).
Scally, S. W. et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210, 2569–2582 (2013).
van Lummel, M. et al. Post-translational modification of HLA-DQ binding islet-autoantigens in type 1 diabetes. Diabetes 63, 237–247 (2014).
Gascoigne, N. R. & Palmer, E. Signaling in thymic selection. Curr. Opin. Immunol. 23, 207–212 (2011).
Bains, I., van Santen, H. M., Seddon, B. & Yates, A. J. Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. PLoS Comput. Biol. 9, e1003102 (2013).
Org, T. et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9, 370–376 (2008).
Koh, A. S. et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl Acad. Sci. USA 105, 15878–15883 (2008).
Abramson, J., Giraud, M., Benoist, C. & Mathis, D. Aire's partners in the molecular control of immunological tolerance. Cell 140, 123–135 (2010).
Giraud, M. et al. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc. Natl Acad. Sci. USA 109, 535–540 (2012).
Danso-Abeam, D., Humblet-Baron, S., Dooley, J. & Liston, A. Models of aire-dependent gene regulation for thymic negative selection. Frontiers Immunol. 2, 14 (2011).
Marrack, P., Ignatowicz, L., Kappler, J. W., Boymel, J. & Freed, J. H. Comparison of peptides bound to spleen and thymus class II. J. Exp. Med. 178, 2173–2183 (1993).
Collado, J. A. et al. Composition of the HLA-DR-associated human thymus peptidome. Eur. J. Immunol. 43, 2273–2282 (2013).
Espinosa, G. et al. Peptides presented by HLA class I molecules in the human thymus. J. Proteomics 94, 23–36 (2013).
Adamopoulou, E. et al. Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nature Commun. 4, 2039 (2013).
Fortier, M. H. et al. The MHC class I peptide repertoire is molded by the transcriptome. J. Exp. Med. 205, 595–610 (2008).
Mester, G., Hoffmann, V. & Stevanovic, S. Insights into MHC class I antigen processing gained from large-scale analysis of class I ligands. Cell. Mol. Life Sci. 68, 1521–1532 (2011).
Millet, V., Naquet, P. & Guinamard, R. R. Intercellular MHC transfer between thymic epithelial and dendritic cells. Eur. J. Immunol. 38, 1257–1263 (2008).
Thymoproteasome and peptidic self
Positive selection of T cells in the thymus is induced by low-affinity TCR recognition of self-peptide-MHC complexes expressed by cortical thymic epithelial cells (cTECs). cTECs express a specialized type of proteasomes, the thymoproteasome, which generates a unique spectrum of MHC class I-associated peptides and plays a critical role in thymic positive selection of CD8 + T cells. However, it remains unclear how the thymoproteasome contributes to the thymic positive selection. More than 30 years ago, the “peptidic self” hypothesis proposed that TCRs recognize MHC-presented peptides only, without interacting with MHC molecules, which turned out to be incorrect. Interestingly, however, by implying that a set of MHC-associated peptides forms immunological self, this hypothesis also predicted that positive selection in the thymus is the primary immune response to “foreign epitope” peptides during T cell development. The thymoproteasome-dependent unique self-peptides may create those foreign epitope peptides displayed in the thymus for positive selection of T cells.
This is a preview of subscription content, access via your institution.
Though a central role for DCs in negative selection of thymocytes is well established, multiple other hematopoietic cell types including B cells, activated T cells, and even thymocytes themselves are also thought to play a role in the deletion of autoreactive T cells in the thymus (5, 8-13, 25-28). Despite the diversity of cells that can support negative selection in the thymus, cTECs do not support deletion of self-reactive thymocytes even when presenting high affinity antigen (1-4, 7). One striking difference between DCs and cTECs is the inability of the later to provide a strong “stop signal” to promote stable thymocyte-cTEC interactions (7). Whether stable conjugate formation is characteristic of other cellular interactions that promote negative selection was not known. Here we show that thymocytes presenting high-affinity antigen can support efficient negative selection that is associated with stable thymocyte-thymocyte interactions and sustained Ca 2+ signaling.
Thymocytes lack many features of professional antigen presenting cells, including expression of co-stimulatory ligands that can promote negative selection (36-40). Moreover, when confronted by broadly distributed agonist peptide, cortical thymocytes preferentially arrest adjacent to DCs, implying that DCs induce a more potent migratory stop signal compared to other peptide presenting cells, including thymocytes, in the vicinity (7). In spite of this, we find that thymocytes can support prolonged peptide-specific contacts with other thymocytes presenting high affinity ligand and induce negative selection. Interestingly, thymocytes express SLAM (Signaling Lymphocyte Activation Molecule) receptors, a family of proteins that stabilize cellular contacts via homotypic interactions and play an essential role in T cell-B cell interactions and thymocyte-driven selection of innate-like T cell subsets (41-47). It is tempting to speculate that homotypic SLAM family interactions may help to stabilize thymocyte-thymocyte contacts that drive negative selection.
Our data have relevance for the role of direct versus indirect antigen presentation during negative selection. Thymic DCs are well equipped to directly present MHC class I associated peptides derived from proteins expressed by the DCs themselves. However, for thymocyte-specific proteins, it is unclear whether peptides are presented directly by thymocytes, or whether protein or peptide-MHC complexes are transferred to DCs for presentation. Although we cannot rule out the possibility that antigen-loaded thymocytes transfer peptide-MHC complexes to thymic DCs, the stability of thymocyte-thymocyte interactions and persistent elevated Ca 2+ levels strongly support a direct presentation route for thymocyte-driven negative selection in this system.
For MHC class II associated antigens, direct presentation by thymocytes likely does not occur in mice given that mouse thymocytes do not express detectable levels of MHC class II. Moreover, the tolerance of CD8, but not CD4, T cells to thymocyte / T cell-specific expression of an MHC class I protein argues that neither efficient transfer of antigen to DCs, nor direct presentation of class II associated antigens by thymocytes occurs in the mouse system (25-28). However, it is interesting to consider that in humans, direct presentation by thymocytes, may play a role in both MHC class I and II tolerance, given that human thymocytes express MHC class II (14-17).
Whether self-peptide presenting thymocytes share the burden of negative selection or act more as a “safety net” during negative selection remains to be determined. Our results indicate that thymocytes themselves can support efficient negative selection, and suggests yet another layer of regulation to prevent self-reactive T cells from leaving the thymus. The thymocyte-mediated negative selection we report here may be particularly relevant for tolerance to thymocyte specific proteins, such as TCR. A number of different hematopoietic cell subsets have now been identified that can support negative selection. These cells are quite diverse and the characteristics that allow these hematopoietic cells, and not cTECs, to support the stable interactions necessary to support efficient negative selection remain to be determined.
Positive selection thymus
Positive selection occurs in the cortex and negative selection occurs in the medulla of the thymus. After this process T cells that have survived leave the thymus, regulated by sphingosine-1-phosphate. Further maturation occurs in the peripheral circulation Low-affinity TCR engagement with self-peptide-MHC complexes mediates positive selection, a process that primarily occurs in the thymic cortex. Massive efforts exerted by many laboratories have led to the characterization of peptides that can induce positive selection
Positive selection in the thymus: an enigma wrapped in a
- Recent data suggest that cortical thymic epithelial cells (cTECs) use unique pathways of self-antigen processing to generate peptide-MHC complexes for positive selection. Thymic dendritic cells..
- Positive Selection of T Cells. T cell precursors differentiate into CD4 + or CD8 + T cells in the cortex of the thymus. Conventional αβ T cells express a TCR that is randomly generated by the recombination of V, D, and J (or for the α chain, V and J only) segments by the recombination-activating genes RAG1 and RAG2
- deletionofautoreactivecells (negative selection), and major histocompatibility complex (MHC) restric-tion (i.e., selection ofthymocytes able to recognize self-MHC molecules, called positive selection), and relies on the concept that whereas receptor-antigen bindingmightcauseT-cellactivationintheperiphery, a similar interaction in the thymus may cause thymocyte death
- dre hos vuxna. Brässen hos andra däggdjur kan användas som mat. Exempelvis kalvbräss betraktas som en delikatess. Ur kalvbräss kan också framställas ett extrakt kallat THX som sades motverka cancer.
Positive Selection and Negative Selection of T Cells. The thymus is essentially a critical organ of the immune system. However, it is also part of the lymphatic system because it belongs to the entire network of organs and tissues that connects the immune system and the circulatory system Positive selection The process by which immature double-positive thymocytes expressing T cell receptors with intermediate affinity and/or avidity for self-peptide-MHC complexes are induced to differentiate into mature single-positive thymocytes. Antigen presentation in the thymus for positive selection and central tolerance inductio A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymocytes into mature T cells according to either negative or positive selection. This selection process is vitally important in shaping the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign. Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. Nishimura H(1), Honjo T, Minato N. Author information: (1)Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan Positive Selection in the Thymus: An Enigma Wrapped in a Mystery Stephen M. Hedrick O ne of the many mysteries that loomed over the ﬁeld of immunology in its dark ages (that period prior to characterization of the TCR and peptide binding by MHC molecules) was the process of T cell development and selection of the receptor repertoire in the thymus
Thymus - Wikipedi
Selection of the T cell repertoire in the thymus involves two steps. First, positive selection promotes the survival of cells binding thymic self-MHC-peptide complexes with sufficient affinity Positive selection of T cells is the maturation process of thymocytes or the immature T cells in the thymus. Hematopoietic stem cells in the bone marrow differentiate into the lymphoid progenitor cells called thymocytes. Significantly, the earliest stages of these thymocytes express neither CD4 or CD8 receptors Thymus-speciﬁc serine protease regulates positive selection of a subset of CD41 thymocytes Julien Gommeaux 1,2,3,4,5, Claude Gre´goire 3,4,5, CD4 1cell positive selection, whereas selection of CD8 cells was unaffected. These data support the involvement of TSSP in intra-thymic antigen presentation by MHC class II molecules Im Thymus werden über 95 Prozent aller jungen T-Zellen ausgemerzt, in Vorgängen, die positive Selektion und negative Selektion heißen. Blöd, wenn man sich vor Jahren entschieden hat, die Zellen des Immunsystems als niedliche froschähnliche Wesen darzustellen Model of differential signaling in the thymus. ( A ) Positive selection: A low-affinity ligand stimulates the TCR, which transmits a signal via the TCR α CPM, CD3 γ -ITAM, and CD3 δ
Generation of Peptides That Promote Positive Selection in
Eine Blut-Thymus-Schranke verhindert den Kontakt zu körperfremden Antigenen. Jene Klone von Lymphozyten, die körpereigene MHC-Moleküle erkennen können und damit funktionstüchtig sind, werden dann vermehrt - alle anderen Klone werden in den programmierten Zelltod geschickt (positive Selektion) Positive Selektion: Unter positiver Selektion versteht man die Selektion von Thymozyten durch kortikale Thymusepithelzellen. Sie präsentieren Peptide im Komplex mit MHC -Molekülen auf ihrer Oberfläche und erkennen, mit welcher Affinität die noch unreifen T-Zellen an diese Peptid/MHC-Komplexe binden CD2 is expressed at higher levels on mature thymocytes compared with their immature precursors.12 To study the relationship between positive selection and CD2 upregulation in more detail, we have compared the level of CD2 expressed by CD4 + CD8 + H-Y TCR + thymocytes in H-2 b or H-2 d thymi, because positive selection of cells expressing the H-Y TCR occurs in the former, but not in the latter
BECAUSE of positive and negative selection to molecules of the major histocompatibility complex (MHC)1, only a small propor-tion of the massive numbers of T cells generated in the thymus are. Unreife T-Zellen wandern über die Blutbahn aus dem Knochenmark in die Thymus-Rinde ein, bewegen sich dann in Richtung Mark und durchlaufen dabei eine doppelte Selektion. Im ersten Schritt prüfen die kortikalen Thymus-Epithelzellen, welche der T-Zellen in der Lage sind, an MHC-Moleküle zu binden . thymus: A ductless gland consisting mainly of primary lymphatic tissue that is the site of lymphocyte maturation and selection. negative selection: The process by which T cells are screened so that those with a high affinity for binding to self antigens (and potentially causing autoimmunity) are destroyed. Positive selection: The process by which T cells are screened so that only. Der Mensch verfügt wie alle Wirbeltiere über ein adaptives Immunsystem, das sich an neue Krankheitserreger anpassen kann. Die T-Zellen des Immunsystems kontr..
Antigen presentation in the thymus for positive selection
the thymus-speciﬁc catalytic subunit Psmb11 (b5t) that is essential for the production of the unique peptide motifs required for positive selection of CD8T cells . The lysosomal proteases, cathepsin L and Prss16 (also known as 'thymus-speciﬁc serine protease' Tssp), are highly expressed in cTECs and are involved in the positive. POSITIVE SELECTION OF THYMOCYTES 101 In this chapter on the nature of the self-recognition event that promotes maturation of the
$3 TCR+ lineage of thymocytes, we provide a brief overview of T cell development, describe the experiments that demonstrate positive selection, and discuss recent work on the nature of the self-ligand that is recognized in the thymus This process, called positive selection, both rescues thymocytes from programmed cell death and induces their differentiation into mature T cells. Another critical event in thymic development is to prevent maturation of hazardous autoreactive T cells thus, mechanisms exist to eliminate T cells with self-reactive receptors (negative selection)
The Mechanisms of T Cell Selection in the Thymus: Trends
- Negative selection in the thymus The first indication that double-positive T cells could be the precursor population came from the work of Kappler, Roehm and Marrack . Using the KJ23 mAb, they defined the product of a new 150 T cell receptor gene family, Va17a, which is expressed on mature T cells of some, but not all, mouse strains
- In the cortex, thymocytes undergo positive selection by cTECs then migrate to the medulla In the medulla, thymocytes are screened for reactivity to tissue-restricted self antigens expressed by mTECs. Mature T cells exit the thymus via blood or lymphatic vessels in response to a sphingosine-1-phosphate (S1P) gradient
- •Positive selection refers to the selection of thymocytes that are able to bind to, and interact with, self-MHC molecules present on thymic cortical epithelial cells •In positive selection developing thymocytes continue to live if they bind MHC well enough to receive a signal through their TCR. If they don't bind they die by neglec
- ation signals for developing thymocytes. To exa
Positive and Negative Selection . The immature T cells that leave the bone marrow enter the thymus in the cortex (known as the classroom of the thymus). During training, these cells are taught to recognize antigens associated with foreign cells and matter in a process called positive selection. Cells are positively selected for usefulness Negative selection: At this point, those T cells that are strongly activated by self MHC plus self peptides need to be eliminated in the thymus. If they escape this elimination, they may subsequently react against self antigens, and cause Autoimmune disease. In summary, Positive selection selects for those T cells that react with MHC: self antigen Thymic positive and negative selections are two major events that form the peripheral T cell repertoire. Both require interactions of T cell antigen receptors (TCR) and coreceptors on thymocytes with major histocompatibility complex (MHC) and other ligands on thymic antigen-presenting cells (1-4).The outcome of the selection is believed to be determined by the strength of intracellular. The full text of this article hosted at iucr.org is unavailable due to technical difficulties
Kevin W. Tinsley, Changwan Hong, Megan A. Luckey, Joo-Young Park, Grace Y. Kim, Hee-won Yoon, Hilary R. Keller, Andrew J. Sacks, Lionel Feigenbaum, Jung-Hyun Park Ikaros is required to survive positive selection and to maintain clonal diversity during T-cell development in the thymus Positiv selektion sker av epitelceller i Thymus cortex. Om T-cellens TcR binder till [MHC I/II + peptid] på epitelcellen får den en signal att inte genomgå apoptos. T-celler som inte känner något antigen genomgår apoptos As with the positive selection, the negative selection also needs the interaction of a T cell receptor with one of the body's own MHC molecule.In contrast to positive selection, which primarily occurs on the epithelial cells of the thymus, the negative selection happens especially on the surface of other cells, e.g., dendritic cells or macrophages
This education involves deletion of autoreactive cells (negative selection), and major histocompatibility complex (MHC) restriction (i.e., selection of thymocytes able to recognize self-MHC molecules, called positive selection), and relies on the concept that whereas receptor-antigen binding might cause T-cell activation in the periphery, a similar interaction in the thymus may cause. Positive selection of DP T cells to the CD4+ CD8− and CD4− CD8+ simple positive (SP) lineages is a multistep process which involves cellular interactions between thymocytes and stromal cells. Mutant nackt (nkt/nkt) mice have been shown to have a deficiency in the CD4+ CD8− T-cell subset both in the thymus and in the periphery Undersökning av thymus Positiv och negativ selektion genom flödescytometri Qian Hu * 1 , Stephanie A. Nicol * 1 , Alexander Y.W. Suen * 1 , Troy A. Baldwin 1 1 Department of Medical Microbiology and Immunology, University of Albert Positive selection in this system is promiscuous, consistent with a report that selection of T cells expressing a particular TCR is promoted by multiple structurally divergent peptides in an FTOC system it is also reminiscent of the results on mice displaying MHC molecules filled with essentially a single peptide, where a large—but not complete—T cell repertoire was selected, on the.
allogenic Rag deficient thymus, we demonstrated that bone marrow APCs (macrophages and dendritic cells) are unable to mediate positive selection of CD4 + T cells. In other words, Thymic epithelial cells are the unique cells able to mediate positive selection of CD4 + T cells Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Thymus-derived lymphocytes (T cells) recognize antigen in the context of class I or class II molecules encoded by the major histocompatibility complex (MHC) by virtue of the heterodimeric αβ T-cell receptor (TCR) 1,2. CD4 and CDS molecules expressed on the. La sélection positive et négative des cellules T sont deux processus du développement des cellules T, qui se produit dans le thymus. Ici, les thymocytes constituent une grande population de lymphocytes T immatures. Zones clés couvertes. 1. Quelle est la sélection positive des cellules T - Définition, processus, importance 2 Recent advances in our knowledge of the biology of thymic epithelial cells have revealed unique machinery that contributes to positive and negative selection in the thymus. In this article, we summarize recent findings on thymic T-cell selection, focusing on the machinery unique to thymic epithelial cells. central tolerance, cortical thymic.
Differentiation of CD4 + 8 + (double-positive, DP) 1 thymocytes into mature single-positive (SP) CD4 + 8 − and CD4 − 8 + cells involves positive and negative selection and is directed to an array of self-peptides bound to MHC molecules (1-7).Negative selection deletes T cells with high affinity for self-peptides via apoptosis, thus ensuring selftolerance, and is presumed to reflect. Rigorous selection processes in the thymus prevent nonfunctional or harmful T cells from reaching the periphery. Thymocytes that express a TCR with high avidity for self peptides presented by self MHC-encoded molecules are eliminated by TCR-mediated apoptosis (negative selection) Demonstration that immature CD4 + 8+ thymocytes contain T cell precursors that are subjected to positive and negative selection was the major step towards understanding how the adaptive immune system acquires the ability to distinguish foreign or abnormal (mutated or infected) self-cells from normal (healthy) cells. In the present review, the roles of TCR, CD4, CD8, and MHC molecules in.
positive Selektion w [von latein. selectio = Auslese], bezeichnet in der Immunologie den Sachverhalt, daß nur T-Lymphocyten mit Rezeptoren (T-Zell-Rezeptor), die von körpereigenen MHC-Molekülen (Histokompatibilitäts-Antigene) präsentierte Antigene (Antigen-Präsentation) erkennen, im Thymus heranreifen können Cross-reactive public TCR sequences undergo positive selection in the human thymic repertoire. We studied human T cell repertoire formation using high-throughput T cell receptor β (TCRβ) complementarity-determining region 3 (CDR3) sequencing in immunodeficient mice receiving human hematopoietic stem cells (HSCs) and human thymus grafts Beta selection Common lymphoid precursor cells that migrate to the thymus become known as T-cell precursors (or thymocytes) and do not express a T cell receptor. The double negative (DN) stage is focused on producing a functional β- chain whereas the double positive (DP) stage is focused on producing a functional α-chain, ultimately producing a functional αβ T cell receptor These cells are important in the differentiation of the immigrating T cell precursors and their 'education' (positive and negative selection) prior to their migration into the secondary lymphoid tissues. Structure of Thymus. It is a pink, flattened, asymmetrical structure lying between sternum and pericardium in anterior mediastinum Double positive thymocytes that express αβ TCR CD 3 complex and survive thymic selection develop into immature single positive CD 4 + thymocyte or single positive CD 8 + thymocytes. These single positive cells undergo additional negative selection and migrate from the cortex to medulla, where they pass from the thymus into the circulatory system
Read Positive and Negative Selection in the Thymus and the Thymic Paradox on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips
Positive selection The process by which immature CD4 +CD8 cells owing to the deletion of non double-positive thymocytes expressing T cell receptors that are able to recognize thymus of TCR transgenic mice only when the cognate antigen was also expressed via a second transgene15
Cofilin1 is essential for positive selection in the thymus and for the transition of DP cells to CD4SP and CD8SP cells. In the thymus, precursor cells pass several checkpoints on the way to functional T cells. The critical steps are characterised by the sequential expression of the TCR-associated co-receptors CD4 and CD8 Thymus - Histologie. Autor: Andreas Rheinländer • Geprüft von: Stefanie Bauer Zuletzt geprüft: 10. April 2021 Lesezeit: 9 Minuten Der Thymus ist ein parenchymatöses Organ des Immunsystems, das zu den primären lymphatischen Geweben des T-Zell-Systems zählt. Als primäres lymphatisches Organ enthält der Thymus keine retikulären Fasern und keine Lymphfollike T cells are derived from haematopoietic stem cells that are found in the bone marrow. The progenitors of these cells migrate to and colonise the thymus. The developing progenitors within the thymus, also known as thymocytes, undergo a series of maturation steps that can be identified based on the expression of different cell surface markers The thymus also controls the specificity of T cells entering the circulation by means of positive and negative selection. Positive selection involves major histocompatibility complex (MHC) restriction, in which there is clonal expansion only of those T cells capable of recognizing antigen in the context of host MHC 1 and 2 Abstract. To establish an immunocompetent TCR repertoire that is useful yet harmless to the body, a de novo thymocyte repertoire generated through the rearrangement of genes that encode TCR is shaped in the thymus through positive and negative selection
Read Positive Selection of γδ CTL by TL Antigen Expressed in the Thymus, The Journal of Experimental Medicine on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips J. Bill and E. Palmer, Positive selection of CD4+ T cells mediated by MHC class II-bearing stromal cell in the thymus, Nature 341:649 (1989). PubMed CrossRef Google Scholar 35 la centrale: la sélection positive concerne le pré BCR, les Cellules qui sont productives vont survivre. la selection négative concerne les LB immature: elle vont subir une selection negative avec destruction des cellules B qui sont autiréactives (c.à.d) une affinité elevée pr les Ag du soi
Thymus-derived Glucocorticoids Regulate Positive Selection MHC with sufficient avidity to normally result in positive selection. Materials and Methods Mice and Reagents. RAG-2 2 / 2 H-2 d and H-2 b mice bearing TCRs specific for H-Y/Db (12) were bred in our facilities by crossing RAG-2 2 / 2 mice (H-2 b, 129 background, (13)) with H-Y/D b. Lymphocyte T. Un article de Wikipédia, l'encyclopédie libre. Les lymphocytes T, ou cellules T, sont une catégorie de leucocytes qui jouent un grand rôle dans la réponse immunitaire adaptative. « T » est l' abréviation de thymus, l'organe dans lequel leur développement s'achève. Ils sont responsables de l'immunité cellulaire : les. The thymus provides a microenvironment that supports the generation and selection of T cells. Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) are essential components of the thymic microenvironment and present MHC-associated self-antigens to developing thymocytes for the generation of immunocompetent and self-tolerant T cells Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expressio In total, this is 6 MHC I and 6 MHC II genes per cell. The cortical thymic epithelial cell, or CTEC for short, presents all 12 of these MHC molecules, which is important for the positive selection. The double positive T-cell now migrates to the medulla of the thymus, where it will meet medullary thymic epithelial cells
BECAUSE of positive and negative selection to molecules of the major histocompatibility complex (MHC) 1 , only a small propor-tion of the massive numbers of T cells generated in the thymus are selected for export 2,3 . Immature thymocytes have a rapid turnover 2 , and it has long been assumed that most thymocytes die i/i siVw<SUP>4,5</SUP>, presumably from apoptosis<SUP>6</SUP> T cells undergo positive selection in the thymus, which means they a) develop surface antigen receptors b) react against self-antigens c) remain alive but unresponsiv and is essential for positive selection in the thymus Andree Salz1, Christine Gurniak1, Friederike Jönsson2 and Walter Witke1,* ABSTRACT Actin dynamics is essential for T-cell development. We show here that cofilin1 is the key molecule for controlling actin filament turnover in this process. Mice with specific depletion of cofilin1 in thymocyte In positive selection, T cells in the thymus that bind moderately to MHC complexes receive survival signals (middle). However, T cells whose TCRs bind too strongly to MHC complexes, and will likely be self-reactive, are killed in the process of negative selection (bottom) positive and negative T cell selection in the thymus A lymphoid organ is situated in the neck of vertebrates which produces T-lymphocytes for the immune system. The human thymus becomes much smaller at the approach of puberty. Cortex - immature thymocytes, epithelial cells and scattered macrophages
T-Cell Development in the Thymus: Positive Selection Filed under: Background — vesuvias @ 1:02 am Tags: immunology, primer. Phenotypic determination of a T-cell: Positive Selection. Share this: Twitter Facebook Like this positive selection in the thymus which means that they A react strongly against from BIO MISC at Delhi Public School Jagdalpu Positive selection of ab T cells by cortical epithelial cells in the thymus a from BIOL MISC at University of Alaska, Anchorag .org/10.1155/1998/8. (external link) http.
. During positive selection Double-Positive T cells that can recognize self MHC's are selected for proliferation, and those T cells that do not recognize self MHC die via Apoptosis We show that Gli3 activity in thymic epithelial cells (TEC) promotes positive selection and differentiation from CD4+CD8+ to CD4+CD8- single positive (SP4) cell in the fetal thymus and that Gli3 represses Shh Constitutive deletion of Gli3, and conditional deletion of Gli3 from TEC, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not T lymphopoiesis in the thymus was thought to be completed once it reaches the single positive (SP) stage, a stage when T cells are fully mature and waiting to be exported at random or follow a first-in-first-out manner. Recent evidence, however, has revealed that the newly generated SP thymocytes undergo a multistage maturation program in the thymic medulla
T/F: when cells fully mature, they can only recognize peptides presented in the same MHC that it could weakly interact with when differentiated and that drove positive selection negative selection self-reactive thymocytes are deleted during development in the thymus due to strong recognition of MHC:peptid thymus •Positive selection required •Coreceptor expression required (CD4 or CD8) Comparison of B and T cell development. Importance of thymus for T cell development. Thymus structure Cortex= + selection Medulla= - selection. Basic overview of T cell development + selection - selection. Main T cell developmenta Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. H Nishimura Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan Thymic stromal cells and positive selection. APMIS, 2008. Ann Chidgey. Richard Boyd. Ann Chidgey. Richard Boyd. Download with Google Download with Facebook. or. Create a free account to download. Download Full PDF Package. This paper. A short summary of this paper The thymus is composed of two major anatomical areas—an outer region known as the cortex, which contains DN and DP thymocytes, and an inner region known as the medulla, which contains SP thymocytes . Positive selection of thymocytes occurs in the cortex Positive Selection of T Cells Induced by Viral Delivery of Neopeptides to the Thymus Naoko Nakano, Ronald Rooke, Christophe Benoist, Diane Mathis The relation between an antigenic peptide that can stimulate a mature T cell and the natural peptide that promoted selection of this cell in the thymus is still unknown. A
In the current study, we established a novel mouse model, designated TN mice, which intrinsically lacks mature cTECs. We identified the G220R mutation of 㬥t as being primarily responsible for cTEC deficiency in TN mice. Thus, TN is a 㬥t-driven, mature cTEC-deficient mouse strain, which will be useful to investigate the physiological significance of cTECs.
It is interesting to note that in the thymus from tn/tn mice, the compartmentalization of cortex and medulla is readily detectable, despite the loss of mature cTECs. It was reported that outward migration of developing thymocytes from the corticomedullary junction to the cortex requires CXCL12-CXCR4 and CCL25-CCR9 chemokine signals 41 , 42 . However, the expression of CXCL12 and CCL25 in CD205 lo UEA1 − TECs from tn/tn mice is very low, 𢏖 and 0.3%, respectively, compared with that in wild-type mature cTECs. Another thymic chemokine CCL21, which attracts mature CD4SP and CD8SP thymocytes from the cortex to the medulla 5 , is normally produced by mTECs in tn/tn mice. These results demonstrate that the cortex/medulla compartmentalization in the thymus does not require mature cTECs and can be mediated by CD205 lo UEA1 − immature TECs along with CCL21-expressing mTECs. Further studies will be needed to dissect developmental processes of cTECs and to better understand their nature and function.
Although the thymic cortex is apparently formed, cortical T-cell development without mature cTECs is obviously abnormal, as tn/tn mice showed impairment of positive selection of αβT cells. tn/tn mouse thymi showed diminished expression of cathepsin L, Prss16 (also called thymus-specific serine protease), and complete loss of 㬥t-containing thymoproteasomes. Cathepsin L and Prss16 are endosomal/lysosomal proteases highly expressed by cTECs that regulate positive selection of MHC class II-restricted CD4 T cells 12 , 13 . Thymoproteasomes are essential for positive selection of MHC class I-restricted CD8 T cells, likely by producing cTEC-specific MHC class I-bound peptides 8 , 10 , 11 . Our results that tn/tn mice have an altered TCR-Vα and TCR-Vβ distribution of both CD4 and CD8 T cells indicate that cTECs contribute not only to generate the optimum cellularity of T cells but also to shape their αβTCR repertoire, as suggested by previous reports. In addition to the lack of such functional molecules in the cortex, it is also possible that a loss of the cortical epithelial network per se impairs thymocyte development through physical interference with intracortical migration or cellll interactions of cortical thymocytes. Taken together, cortex-resident, immature TECs in tn/tn thymus are incompetent for αβT-cell repertoire formation, even though they are functional in forming the thymic cortex and supporting development of a small fraction of αβT cells, confirming the essential role for cTECs in development and repertoire formation of conventional αβT cells.
To the contrary, negative selection of mtv superantigen-reactive thymocytes occurred normally in tn/tn mice. Indeed, no signs of systemic autoimmunity were detected in tn/tn mice (unpublished observation), indicating that self-tolerance is established in the absence of mature cTECs. Although a recent report indicated that three quarters of negative selection occurs in the cortex 43 , negative selection was not affected in the absence of mature cTECs. Therefore, cortex-resident, immature TECs and/or dendritic cells 44 may induce negative selection of self-reactive thymocytes.
The most unexpected finding from the current study was the influence of mature cTEC deficiency on γδT-cell development. γδT cells generated in the absence of mature cTECs were skewed toward IL-17-producing (γδT17) lineage that expressed an altered γδTCR repertoire. As the development of V㬵 + and V㬱 + γδT cells (mostly non-γδT17 cells) was normal in tn/tn thymus, the influence of mature cTEC deficiency is specific to γδT17 lineage. It was shown that development of γδT cells in the thymus is dependent on IL-7 45 , and expansion and development of γδT17 cells requires IL-7 46 and Dll4-Notch signals 47 , respectively. As tn/tn mice lack mature cTECs that express high levels of IL-7 and Dll4, the increase of γδT17 cells seen in the tn/tn thymus could not be directly attributed to signaling on these molecules. It may be that relatively low levels of expression of IL-7 and Dll4 by immature TECs and mTECs, and also likely by other thymic stromal cells, are sufficient for inducing development of γδT17 cells. Most interestingly, two major subsets of γδT17 cells, V㬶 + cells and V㬴 + cells, are reciprocally differentiated in tn/tn mice. Increased and prolonged production of V㬶 + cells resulted in boosted V㬶 + γδT17-mediated inflammatory responses, and impaired production of V㬴 + cells, which in turn provided protection from V㬴 + γδT17-dependent dermatitis. The altered repertoire of γδT cells in tn/tn mice was due to neither 㬥t deficiency nor reduced mTEC development, as the distribution of V㬴 + and V㬶 + cells was unaffected in 㬥t-deficient mice and mTEC-reduced, MHC-deficient mice, and the altered γδT-cell repertoire in tn/tn mice was not restored by sRANKL-mediated enhancement of mTEC differentiation. These results suggest that mature cTECs play roles in repressing the development of V㬶 + cells and promoting that of V㬴 + cells, although it is also possible that cortex-resident, immature TECs in tn/tn mice have reciprocal functions and that partly defective development of (likely RANKL-independent) mTECs in tn/tn mice caused the γδT17 repertoire alteration. A recent study showed a differential developmental requirement for V㬴 + and V㬶 + γδT17 cells V㬶 + γδT17 cells absolutely require fetal thymus for their development, whereas V㬴 + γδT17 cells can be generated in adult thymus 48 . Thus, it is suggested that the thymus from adult tn/tn mice provides fetal type microenvironment that supports predominant development of V㬶 + γδT17 cells.
Our results first reveal that cTECs determine the balance between V㬴 + and V㬶 + γδT-cell development, which is important for properly mounting inflammatory responses. The mechanisms by which cTECs regulate the γδT17 TCR repertoire remain to be elucidated. Mature cTECs and immature TECs may express different cell-surface proteins, such as Skint family proteins 49 , or as of yet unidentified selecting ligand molecule(s), that mediate differentiation or deletion of V㬴 + or V㬶 + γδT cells for example, as mTECs support maturation of V㬵 + cells via expression of Skint1 17 , 50 . The conversion of the Vγ repertoire in tn/tn mice could be attributed to the alternation of interaction between the γδTCRs and its putative ligands on TECs, because recent studies proposed that strength of ligand–γδTCR interaction controls lineage commitment and specification of effector fate of γδT cells 16 , 20 , 51 . It is also possible that restricted access of developing γδT cells to cTECs 52 or reduced negative feedback of γδT17 development by αβT cells 33 may be responsible for the repertoire conversion in tn/tn mice. We observed reduced expression of the transcription factor Sox13 in V㬴 + γδT cells from cTEC-deficient tn/tn mice. Interestingly, deficiency of Sox13 in mice resulted in the loss of V㬴 + γδT17 cell development but a partial reduction of V㬴 − (likely to be V㬶 + ) γδT17 cells 35 , 36 . Therefore, the conversion of the γδT17 repertoire in tn/tn mice could be partly explained by the decrease of Sox13, caused by the absence of proper interaction with cTECs.
Taken together, the present study, utilizing a newly established mouse strain that lacks mature cTECs, provides novel evidence for γδT-cell repertoire determination by thymic epithelium. cTECs are required for the shaping of the TCR repertoire, not only of conventional αβT-cell subsets, but also of an “innate-type” γδT-cell subset programmed for IL-17 production. Future studies to clarify the molecular mechanisms should unveil developmental rules for γδT cells that can be applied to γδT-cell-based immunotherapies.
AWB was supported by the President's Initiative and Networking Fund of the Helmholtz Association of German Research Centers (HGF) under contract number VH-GS-202. This work was supported by the Helmholtz portfolio program Metabolic Dysfunction, the Fritz-Thyssen foundation and the Deutsche Forschungsgemeinschaft (SCHM1586/3-1) to IS.
Autophagy in T-cell development, differentiation and function. T cells originate from bone marrow-derived pluripotent HSCs. These differentiate into CLPs that enter the thymus and differentiate into thymocytes. Thymocytes undergo selection processes that are dependent on interactions with thymic APCs and TECs. Mature T cells leave the thymus and enter the periphery to become effector T cells that are activated and proliferated upon antigen encounter. After an immune response, most effecter T cells die and few survive as memory T cells. The role of autophagy is indicated at the different steps of a T cells’ life. See text for further details.