Selection of regulatory T cells in the thymus (original) (raw)

• Wing, K. & Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nature Immunol. 11, 7–13 (2010).
  Article CAS Google Scholar
• Rudensky, A. Y. Regulatory T cells and Foxp3. Immunol. Rev. 241, 260–268 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• d'Hennezel, E. et al. FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome. N. Engl. J. Med. 361, 1710–1713 (2009).
  Article CAS PubMed Google Scholar
• Ramsdell, F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19, 165–168 (2003).
  Article CAS PubMed Google Scholar
• Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol. 8, 191–197 (2007).
  CAS Google Scholar
• Nishizuka, Y. & Sakakura, T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755 (1969).
  Article CAS PubMed Google Scholar
• Asano, M., Toda, M., Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J. Exp. Med. 184, 387–396 (1996).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Haribhai, D. et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35, 109–122 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Gershon, R. K. & Kondo, K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18, 723–737 (1970).
  CAS PubMed PubMed Central Google Scholar
• Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). J. Immunol. 155, 1151–1164 (1995).
  CAS PubMed Google Scholar
• Itoh, M. et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol. 162, 5317–5326 (1999).
  CAS PubMed Google Scholar
• Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunol. 2, 301–306 (2001).
  Article CAS Google Scholar
• Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nature Immunol. 3, 756–763 (2002).
  Article CAS Google Scholar
• Knoechel, B., Lohr, J., Kahn, E., Bluestone, J. A. & Abbas, A. K. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J. Exp. Med. 202, 1375–1386 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Baldwin, T. A., Sandau, M. M., Jameson, S. C. & Hogquist, K. A. The timing of TCRα expression critically influences T cell development and selection. J. Exp. Med. 202, 111–121 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Wong, J. et al. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J. Immunol. 178, 7032–7041 (2007).
  Article CAS PubMed Google Scholar
• Hsieh, C.-S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).
  Article CAS PubMed Google Scholar
• Shih, F. F., Mandik-Nayak, L., Wipke, B. T. & Allen, P. M. Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells. J. Exp. Med. 199, 323–335 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Van Santen, H.-M., Benoist, C. & Mathis, D. Number of T reg cells that differentiate does not increase upon encounter of agonist ligand on thymic epithelial cells. J. Exp. Med. 200, 1221–1230 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Pennington, D. J. et al. Early events in the thymus affect the balance of effector and regulatory T cells. Nature 444, 1073–1077 (2006).
  Article CAS PubMed Google Scholar
• Pacholczyk, R. et al. Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity 27, 493–504 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Bautista, J. L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nature Immunol. 10, 610–617 (2009).
  Article CAS Google Scholar
• 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). By using Nur77 –GFP as a reporter for TCR stimulation, this study correlated the level of TCR signal received with the potential for T Reg cell differentiation.
  Article CAS PubMed PubMed Central Google Scholar
• Dipaolo, R. J. & Shevach, E. M. CD4+ T-cell development in a mouse expressing a transgenic TCR derived from a Treg. Eur. J. Immunol. 39, 234–240 (2008).
  Article CAS Google Scholar
• Killebrew, J. R. et al. A self-reactive TCR drives the development of Foxp3+ regulatory T cells that prevent autoimmune disease. J. Immunol. 187, 861–869 (2011).
  Article CAS PubMed Google Scholar
• 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. Nature Immunol. 7, 401–410 (2006).
  Article CAS Google Scholar
• Lio, C. W. & Hsieh, C. S. Becoming self-aware: the thymic education of regulatory T cells. Curr. Opin. Immunol. 23, 213–219 (2011).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS Google Scholar
• 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).
  Article CAS Google Scholar
• Long, M., Park, S. G., Strickland, I., Hayden, M. S. & Ghosh, S. Nuclear factor-κB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921–931 (2009).
  Article CAS PubMed Google Scholar
• Cozzo Picca, C. et al. CD4+CD25+Foxp3+ regulatory T cell formation requires more specific recognition of a self-peptide than thymocyte deletion. Proc. Natl Acad. Sci. USA 108, 14890–14895 (2011). This study demonstrated that, in addition to avidity, the quality or affinity of the interaction between a TCR and a peptide–MHC complex is important for thymic T Reg cell selection.
  Article PubMed PubMed Central Google Scholar
• Riley, M. P. et al. Graded deletion and virus-induced activation of autoreactive CD4+ T cells. J. Immunol. 165, 4870–4876 (2000).
  Article CAS PubMed Google Scholar
• Hinterberger, M. et al. Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nature Immunol. 11, 512–519 (2010). By diminishing antigen presentation by mTECs using shRNA-mediated knockdown of CIITA expression, this group showed that decreasing the avidity of the mTEC–thymocyte interaction can shift the cell fate from deletion to T Reg cell selection.
  Article CAS Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Romagnoli, P., Tellier, J. & van Meerwijk, J. P. Genetic control of thymic development of CD4+CD25+FoxP3+ regulatory T lymphocytes. Eur. J. Immunol. 35, 3525–3532 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006).
  Article CAS PubMed Google Scholar
• Palmer, E. & Naeher, D. Affinity threshold for thymic selection through a T-cell receptor–co-receptor zipper. Nature Rev. Immunol. 9, 207–213 (2009).
  CAS Google Scholar
• Gottschalk, R. A., Corse, E. & Allison, J. P. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J. Exp. Med. 207, 1701–1711 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• 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, 1–12 (2011).
  Article Google Scholar
• Le Borgne, M. et al. The impact of negative selection on thymocyte migration in the medulla. Nature Immunol. 10, 823–830 (2009).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Lathrop, S. K., Santacruz, N. A., Pham, D., Luo, J. & Hsieh, C. S. Antigen-specific peripheral shaping of the natural regulatory T cell population. J. Exp. Med. 205, 3105–3117 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Taguchi, O. et al. Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens. Immunology 82, 365–369 (1994).
  CAS PubMed PubMed Central Google Scholar
• Seddon, B. & Mason, D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J. Exp. Med. 189, 877–882 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Wheeler, K. M., Samy, E. T. & Tung, K. S. Cutting edge: normal regional lymph node enrichment of antigen-specific regulatory T cells with autoimmune disease-suppressive capacity. J. Immunol. 183, 7635–7638 (2009).
  Article CAS PubMed Google Scholar
• Rosenblum, M. D. et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538–542 (2011). This study showed that T Reg cells can differentiate into cells with 'memory' characteristics that reside in the tissue and diminish recurrent autoimmune responses.
  Article CAS PubMed PubMed Central Google Scholar
• Bopp, T. et al. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. J. Exp. Med. 201, 181–187 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nature Immunol. 9, 432–443 (2008).
  Article CAS Google Scholar
• Haxhinasto, S., Mathis, D. & Benoist, C. The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565–574 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nature Immunol. 12, 295–303 (2011).
  Article CAS Google Scholar
• Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nature Immunol. 11, 618–627 (2010).
  CAS Google Scholar
• Kerdiles, Y. M. et al. Foxo transcription factors control regulatory T cell development and function. Immunity 33, 890–904 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Harada, Y. et al. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J. Exp. Med. 207, 1381–1391 (2010). References 58–60 were three independent studies that demonstrated the importance of FOXO in the thymic development of T Reg cells.
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Ruan, Q. et al. Development of Foxp3+ regulatory T cells is driven by the c-Rel enhanceosome. Immunity 31, 932–940 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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). References 37, 62 and 63 demonstrated that the NF-κB factor cREL is necessary and sufficient for inducing the differentiation of thymic T Reg cells. In addition, the analysis of the Foxp3 locus in this study revealed a conserved non-coding sequence (CNS3) as an important cis -element for the induction of Foxp3 expression during thymic T Reg cell development.
  Article CAS PubMed PubMed Central Google Scholar
• Feuerer, M., Hill, J. A., Mathis, D. & Benoist, C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nature Immunol. 10, 689–695 (2009).
  Article CAS Google Scholar
• Lohr, J., Knoechel, B., Kahn, E. C. & Abbas, A. K. Role of B7 in T cell tolerance. J. Immunol. 173, 5028–5035 (2004).
  Article CAS PubMed Google Scholar
• 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. Nature Immunol. 6, 152–162 (2005).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Grewal, I. S. & Flavell, R. A. CD40 and CD154 in cell-mediated immunity. Annu. Rev. Immunol. 16, 111–135 (1998).
  Article CAS PubMed Google Scholar
• Spence, P. J. & Green, E. A. Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. Proc. Natl Acad. Sci. USA 105, 973–978 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100–111 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005).
  Article CAS Google Scholar
• Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).
  Article CAS PubMed Google Scholar
• Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R. & Farrar, M. A. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280–290 (2007). Together with reference 70, this study demonstrates that the development of thymic T Reg cells can be divided into at least two steps based on the dependence on TCR stimulation: a proper TCR signal probably instructs thymocytes to develop into FOXP3 − T Reg cell precursors, which then express FOXP3 after acquiring an IL-2 signal without a continuous TCR signal.
  Article CAS PubMed Google Scholar
• Zorn, E. et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368–4375 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Schallenberg, S., Tsai, P. Y., Riewaldt, J. & Kretschmer, K. Identification of an immediate Foxp3− precursor to Foxp3+ regulatory T cells in peripheral lymphoid organs of nonmanipulated mice. J. Exp. Med. 207, 1393–1407 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
  Article CAS PubMed Google Scholar
• Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Liu, Y. et al. A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nature Immunol. 9, 632–640 (2008).
  Article CAS Google Scholar
• Ouyang, W., Beckett, O., Ma, Q. & Li, M. O. Transforming growth factor-β signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32, 642–653 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Wirnsberger, G., Hinterberger, M. & Klein, L. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89, 45–53 (2011).
  Article PubMed Google Scholar
• Bensinger, S. J., Bandeira, A., Jordan, M. S., Caton, A. J. & Laufer, T. M. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4+ CD25+ immunoregulatory T cells. J. Exp. Med. 194, 427–438 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005).
  Article CAS PubMed Google Scholar
• Liston, A. et al. Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc. Natl Acad. Sci. USA 105, 11903–11908 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wan, Y. Y. & Flavell, R. A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl Acad. Sci. USA 102, 5126–5131 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Cabarrocas, J. et al. Foxp3+ CD25+ regulatory T cells specific for a neo-self-antigen develop at the double-positive thymic stage. Proc. Natl Acad. Sci. USA 103, 8453–8458 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, H. M. & Hsieh, C. S. Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J. Immunol. 183, 2261–2266 (2009).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS Google Scholar
• Proietto, A. I. et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl Acad. Sci. USA 105, 19869–19874 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Koble, C. & Kyewski, B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505–1513 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed PubMed Central Google Scholar
• Daniely, D., Kern, J., Cebula, A. & Ignatowicz, L. Diversity of TCRs on natural Foxp3+ T cells in mice lacking Aire expression. J. Immunol. 184, 6865–6873 (2010).
  Article CAS PubMed Google Scholar