Kappler, J. W., Roehm, N. & Marrack, P. T cell tolerance by clonal elimination in the thymus. Cell 49, 273–280 (1987).
Kisielow, P., Bluthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 (1988).
Modigliani, Y. et al. Lymphocytes selected in allogeneic thymic epithelium mediate dominant tolerance toward tissue grafts of the thymic epithelium haplotype. Proc. Natl Acad. Sci. USA 92, 7555–7559 (1995).
Ohki, H., Martin, C., Corbel, C., Coltey, M. & Le Douarin, N. M. Tolerance induced by thymic epithelial grafts in birds. Science 237, 1032–1035 (1987).
Salaun, J. et al. Thymic epithelium tolerizes for histocompatibility antigens. Science 247, 1471–1474 (1990).
Fowell, D. & Mason, D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med. 177, 627–636 (1993).
Powrie, F., Leach, M. W., Mauze, S., Caddle, L. B. & Coffman, R. L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5, 1461–1471 (1993).
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
Thornton, A. M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).
Weiss, J. M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723–1742 (2012).
Hsieh, C. S., Lee, H. M. & Lio, C. W. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12, 157–167 (2012).
Klein, L. & Jovanovic, K. Regulatory T cell lineage commitment in the thymus. Semin. Immunol. 23, 401–409 (2011).
Bautista, J. L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. 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).
Hsieh, C. S., Zheng, Y., Liang, Y., Fontenot, J. D. & Rudensky, A. Y. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7, 401–410 (2006).
Pacholczyk, R., Ignatowicz, H., Kraj, P. & Ignatowicz, L. Origin and T cell receptor diversity of Foxp3+ CD4+ CD25+ T cells. Immunity 25, 249–259 (2006).
Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 3, 756–763 (2002).
Jordan, M. S. et al. Thymic selection of CD4+ CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).
Klein, L., Khazaie, K. & von Boehmer, H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc. Natl Acad. Sci. USA 100, 8886–8891 (2003).
Picca, C. C. et al. Thymocyte deletion can bias Treg formation toward low-abundance self-peptide. Eur. J. Immunol. 39, 3301–3306 (2009).
Legoux, F. P. et al. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43, 896–908 (2015).
Malhotra, D. et al. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol. 17, 187–195 (2016). References 21 and 22 indicate that in the polyclonal repertoire, a TRA-like pattern of antigen expression favours T
reg cell induction over deletion, which reveals a correlation between self-antigen expression patterns and the mode of CD4
+ T cell tolerance.
Malchow, S. et al. Aire enforces immune tolerance by directing autoreactive T cells into the regulatory T cell lineage. Immunity 44, 1102–1113 (2016).
Perry, J. S. et al. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41, 414–426 (2014).
Yang, S., Fujikado, N., Kolodin, D., Benoist, C. & Mathis, D. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348, 589–594 (2015).
Anderson, M. S. et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 23, 227–239 (2005).
DeVoss, J. et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203, 2727–2735 (2006).
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).
Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354 (2003).
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).
Kurd, N. & Robey, E. A. T cell selection in the thymus: a spatial and temporal perspective. Immunol. Rev. 271, 114–126 (2016).
Petrie, H. T. & Zuniga-Pflucker, J. C. Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25, 649–679 (2007).
Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).
Ebert, P. J., Ehrlich, L. I. & Davis, M. M. Low ligand requirement for deletion and lack of synapses in positive selection enforce the gauntlet of thymic T cell maturation. Immunity 29, 734–745 (2008).
Peterson, D. A., DiPaolo, R. J., Kanagawa, O. & Unanue, E. R. Cutting edge: negative selection of immature thymocytes by a few peptide-MHC complexes: differential sensitivity of immature and mature T cells. J. Immunol. 162, 3117–3120 (1999).
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-kappaB. J. Exp. Med. 210, 269–285 (2013). This study reveals the extent, stage and molecular nature of two distinct waves of clonal deletion in the normal thymus.
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). This paper uses an elegant method to assess the quantitative impact of clonal deletion at different stages of thymocyte differentiation.
Fontenot, J. D., Dooley, J. L., Farr, A. G. & Rudensky, A. Y. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202, 901–906 (2005).
Lee, H. M. & Hsieh, C. S. Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J. Immunol. 183, 2261–2266 (2009).
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).
Kishimoto, H. & Sprent, J. Negative selection in the thymus includes semimature T cells. J. Exp. Med. 185, 263–271 (1997).
Le Borgne, M. et al. The impact of negative selection on thymocyte migration in the medulla. Nat. Immunol. 10, 823–830 (2009).
Ueda, Y. et al. Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus. Nat. Commun. 3, 1098 (2012).
Dzhagalov, I. L., Chen, K. G., Herzmark, P. & Robey, E. A. Elimination of self-reactive T cells in the thymus: a timeline for negative selection. PLOS Biol. 11, e1001566 (2013).
Sauer, S. et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl Acad. Sci. USA 105, 7797–7802 (2008). This study uses in vitro approaches to suggest that temporal aspects of TCR signalling might be crucial for FOXP3 induction during T
reg cell differentiation.
Khailaie, S., Robert, P. A., Toker, A., Huehn, J. & Meyer-Hermann, M. A signal integration model of thymic selection and natural regulatory T cell commitment. J. Immunol. 193, 5983–5996 (2014). This is a bioinformatic study that introduces a TCR signal integration model of thymic selection, describing how thymocyte cell fates might be based upon the TCR stimulation history.
Au-Yeung, B. B. et al. Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development. Nat. Immunol. 15, 687–694 (2014).
Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006).
Mariathasan, S. et al. Duration and strength of extracellular signal-regulated kinase signals are altered during positive versus negative thymocyte selection. J. Immunol. 167, 4966–4973 (2001).
Wu, L. & Shortman, K. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17, 304–312 (2005).
Hu, Z. et al. CCR7 modulates the generation of thymic regulatory T cells by altering the composition of the thymic dendritic cell compartment. Cell Rep. 21, 168–180 (2017).
Hadeiba, H. et al. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36, 438–450 (2012).
Yamano, T. et al. Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42, 1048–1061 (2015).
Yamano, T., Steinert, M. & Klein, L. Thymic B cells and central T cell tolerance. Front. Immunol. 6, 376 (2015).
Hinterberger, M. et al. Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nat. Immunol. 11, 512–519 (2010).
Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).
van Meerwijk, J. P. et al. Quantitative impact of thymic clonal deletion on the T cell repertoire. J. Exp. Med. 185, 377–383 (1997).
Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).
Burchill, M. A. et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28, 112–121 (2008).
Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100–111 (2008).
Bending, D. et al. A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo. J. Cell. Biol. 217, 2931–2950 (2018).
Marshall, D., Sinclair, C., Tung, S. & Seddon, B. Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells. J. Immunol. 193, 5525–5533 (2014).
Tai, X. et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38, 1116–1128 (2013).
Bayer, A. L., Lee, J. Y., de la Barrera, A., Surh, C. D. & Malek, T. R. A function for IL-7R for CD4+CD25+Foxp3+ T regulatory cells. J. Immunol. 181, 225–234 (2008).
Vang, K. B. et al. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J. Immunol. 181, 3285–3290 (2008).
Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368–4375 (2007).
Bayer, A. L., Yu, A., Adeegbe, D. & Malek, T. R. Essential role for interleukin-2 for CD4+CD25+ T regulatory cell development during the neonatal period. J. Exp. Med. 201, 769–777 (2005).
Weist, B. M., Kurd, N., Boussier, J., Chan, S. W. & Robey, E. A. Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat. Immunol. 16, 635–641 (2015).
Owen, D. L. et al. Identification of cellular sources of IL-2 needed for regulatory T cell development and homeostasis. J. Immunol. 200, 3926–3933 (2018).
Boursalian, T. E., Golob, J., Soper, D. M., Cooper, C. J. & Fink, P. J. Continued maturation of thymic emigrants in the periphery. Nat. Immunol. 5, 418–425 (2004).
Yang-Snyder, J. A. & Rothenberg, E. V. Spontaneous expression of interleukin-2 in vivo in specific tissues of young mice. Dev. Immunol. 5, 223–245 (1998).
Wuest, S. C. et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat. Med. 17, 604–609 (2011).
Thiault, N. et al. Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors. Nat. Immunol. 16, 628–634 (2015). The results from this paper introduce the concept of feedback inhibition of intrathymic T
reg cell differentiation by recirculating T
reg cells from the periphery.
Cowan, J. E. et al. Aire controls the recirculation of murine Foxp3+ regulatory T cells back to the thymus. Eur. J. Immunol. 48, 844–854 (2018).
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).
D’Cruz, L. M. & Klein, L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6, 1152–1159 (2005).
Kishimoto, H. & Sprent, J. Several different cell surface molecules control negative selection of medullary thymocytes. J. Exp. Med. 190, 65–73 (1999).
Rubin, R. L. & Hermanson, T. M. Plasticity in the positive selection of T cells: affinity of the selecting antigen and IL-7 affect T cell responsiveness. Int. Immunol. 17, 959–971 (2005).
Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).
Tai, X., Cowan, M., Feigenbaum, L. & Singer, A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat. Immunol. 6, 152–162 (2005).
Lio, C. W., Dodson, L. F., Deppong, C. M., Hsieh, C. S. & Green, J. M. CD28 facilitates the generation of Foxp3− cytokine responsive regulatory T cell precursors. J. Immunol. 184, 6007–6013 (2010).
Vang, K. B. et al. Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J. Immunol. 184, 4074–4077 (2010).
Hinterberger, M., Wirnsberger, G. & Klein, L. B7/CD28 in central tolerance: costimulation promotes maturation of regulatory T cell precursors and prevents their clonal deletion. Front. Immunol. 2, 30 (2011).
Murray, M. E. et al. CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. Blood 123, 3770–3779 (2014).
Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).
Ouyang, W., Beckett, O., Ma, Q. & Li, M. O. Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32, 642–653 (2010).
Punt, J. A., Havran, W., Abe, R., Sarin, A. & Singer, A. T cell receptor (TCR)-induced death of immature CD4+CD8+ thymocytes by two distinct mechanisms differing in their requirement for CD28 costimulation: implications for negative selection in the thymus. J. Exp. Med. 186, 1911–1922 (1997).
Dautigny, N., Le Campion, A. & Lucas, B. Timing and casting for actors of thymic negative selection. J. Immunol. 162, 1294–1302 (1999).
Jones, L. A., Izon, D. J., Nieland, J. D., Linsley, P. S. & Kruisbeek, A. M. CD28–B7 interactions are not required for intrathymic clonal deletion. Int. Immunol. 5, 503–512 (1993).
Page, D. M., Kane, L. P., Allison, J. P. & Hedrick, S. M. Two signals are required for negative selection of CD4+CD8+ thymocytes. J. Immunol. 151, 1868–1880 (1993).
Tan, R., Teh, S. J., Ledbetter, J. A., Linsley, P. S. & Teh, H. S. B7 costimulates proliferation of CD4–8+ T lymphocytes but is not required for the deletion of immature CD4+8+ thymocytes. J. Immunol. 149, 3217–3224 (1992).
Walunas, T. L., Sperling, A. I., Khattri, R., Thompson, C. B. & Bluestone, J. A. CD28 expression is not essential for positive and negative selection of thymocytes or peripheral T cell tolerance. J. Immunol. 156, 1006–1013 (1996).
Pobezinsky, L. A. et al. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat. Immunol. 13, 569–578 (2012). This study reconciles conflicting data on the role of CD28 in clonal deletion.
Collette, Y., Benziane, A., Razanajaona, D. & Olive, D. Distinct regulation of T cell death by CD28 depending on both its aggregation and T cell receptor triggering: a role for Fas–FasL. Blood 92, 1350–1363 (1998).
Li, M. O. & Flavell, R. A. TGF-beta: a master of all T cell trades. Cell 134, 392–404 (2008).
Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).
Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227 (2005).
Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T cell fate. Nature 463, 808–812 (2010).
Li, M. O., Sanjabi, S. & Flavell, R. A. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006).
Marie, J. C., Letterio, J. J., Gavin, M. & Rudensky, A. Y. TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067 (2005).
Liu, Y. et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9, 632–640 (2008).
Chen, W. et al. Requirement for transforming growth factor β1 in controlling T cell apoptosis. J. Exp. Med. 194, 439–453 (2001).
Schlenner, S. M., Weigmann, B., Ruan, Q., Chen, Y. & von Boehmer, H. Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut. J. Exp. Med. 209, 1529–1535 (2012).
Konkel, J. E., Jin, W., Abbatiello, B., Grainger, J. R. & Chen, W. Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. Proc. Natl Acad. Sci. USA 111, E465–E473 (2014).
Chen, W. & Konkel, J. E. Development of thymic Foxp3+ regulatory T cells: TGF-β matters. Eur. J. Immunol. 45, 958–965 (2015).
Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298, 1395–1401 (2002).
Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2, 1032–1039 (2001).
Mathis, D. & Benoist, C. A decade of AIRE. Nat. Rev. Immunol. 7, 645–650 (2007).
Peterson, P., Org, T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat. Rev. Immunol. 8, 948–957 (2008).
Derbinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33–45 (2005).
Takaba, H. et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163, 975–987 (2015).
Sansom, S. N. et al. Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome. Res. 24, 1918–1931 (2014).
Smith, K. M., Olson, D. C., Hirose, R. & Hanahan, D. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int. Immunol. 9, 1355–1365 (1997).
Brennecke, P. et al. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat. Immunol. 16, 933–941 (2015).
Meredith, M., Zemmour, D., Mathis, D. & Benoist, C. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat. Immunol. 16, 942–949 (2015).
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).
Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7, 1092–1100 (2006).
Perry, J. S. A. et al. CD36 mediates cell-surface antigens to promote thymic development of the regulatory T cell receptor repertoire and allo-tolerance. Immunity 48, 923–936 (2018).
Lee, H. M., Bautista, J. L., Scott-Browne, J., Mohan, J. F. & Hsieh, C. S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37, 475–486 (2012).
Simons, D. M. et al. How specificity for self-peptides shapes the development and function of regulatory T cells. J. Leukoc. Biol. 88, 1099–1107 (2010).
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).
Feuerer, M. et al. Enhanced thymic selection of FoxP3+ regulatory T cells in the NOD mouse model of autoimmune diabetes. Proc. Natl Acad. Sci. USA 104, 18181–18186 (2007).
Relland, L. M. et al. Affinity-based selection of regulatory T cells occurs independent of agonist-mediated induction of Foxp3 expression. J. Immunol. 182, 1341–1350 (2009).