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). ArticleCAS 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). ArticleCASPubMed Google Scholar
Ramsdell, F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity19, 165–168 (2003). ArticleCASPubMed 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. Science166, 753–755 (1969). ArticleCASPubMed 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). ArticleCASPubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Haribhai, D. et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity35, 109–122 (2011). ArticleCASPubMedPubMed Central Google Scholar
Gershon, R. K. & Kondo, K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology18, 723–737 (1970). CASPubMedPubMed 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). CASPubMed 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). CASPubMed 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). ArticleCAS 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). ArticleCAS 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). ArticleCASPubMedPubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol.2, 816–822 (2001). ArticleCAS Google Scholar
Pacholczyk, R., Ignatowicz, H., Kraj, P. & Ignatowicz, L. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity25, 249–259 (2006). ArticleCASPubMed 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). ArticleCASPubMed Google Scholar
Hsieh, C.-S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity21, 267–277 (2004). ArticleCASPubMed 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). ArticleCASPubMedPubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Pennington, D. J. et al. Early events in the thymus affect the balance of effector and regulatory T cells. Nature444, 1073–1077 (2006). ArticleCASPubMed 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). ArticleCASPubMedPubMed 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). ArticleCASPubMed 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). ArticleCAS 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 usingNur77–GFP as a reporter for TCR stimulation, this study correlated the level of TCR signal received with the potential for TRegcell differentiation. ArticleCASPubMedPubMed 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). ArticleCAS 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). ArticleCASPubMed 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). ArticleCAS 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). ArticleCASPubMed 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). ArticleCAS 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). ArticleCAS 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. Immunity31, 921–931 (2009). ArticleCASPubMed 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. USA108, 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 TRegcell selection. ArticlePubMedPubMed 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). ArticleCASPubMed 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 TRegcell selection. ArticleCAS 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. USA104, 18181–18186 (2007). ArticleCASPubMedPubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature444, 724–729 (2006). ArticleCASPubMed 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). ArticleCASPubMedPubMed 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). ArticleCAS Google Scholar
Sauer, S. et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl Acad. Sci. USA105, 7797–7802 (2008). ArticleCASPubMedPubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Taguchi, O. et al. Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens. Immunology82, 365–369 (1994). CASPubMedPubMed 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). ArticleCASPubMed Google Scholar
Rosenblum, M. D. et al. Response to self antigen imprints regulatory memory in tissues. Nature480, 538–542 (2011). This study showed that TRegcells can differentiate into cells with 'memory' characteristics that reside in the tissue and diminish recurrent autoimmune responses. ArticleCASPubMedPubMed 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). ArticleCASPubMedPubMed 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). ArticleCAS 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). ArticleCASPubMedPubMed 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). ArticleCAS Google Scholar
Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. NatureImmunol.11, 618–627 (2010). CAS 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 TRegcells. ArticleCASPubMedPubMed 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. USA106, 10278–10283 (2009). ArticleCASPubMedPubMed Central Google Scholar
Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature463, 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 TRegcells. In addition, the analysis of theFoxp3locus in this study revealed a conserved non-coding sequence (CNS3) as an importantcis-element for the induction ofFoxp3expression during thymic TRegcell development. ArticleCASPubMedPubMed 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). ArticleCAS 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). ArticleCASPubMed 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). ArticleCAS 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). ArticleCASPubMed Google Scholar
Grewal, I. S. & Flavell, R. A. CD40 and CD154 in cell-mediated immunity. Annu. Rev. Immunol.16, 111–135 (1998). ArticleCASPubMed Google Scholar
Spence, P. J. & Green, E. A. Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. Proc. Natl Acad. Sci. USA105, 973–978 (2008). ArticleCASPubMedPubMed 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). ArticleCAS 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. Immunity17, 167–178 (2002). ArticleCASPubMed 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 TRegcells 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−TRegcell precursors, which then express FOXP3 after acquiring an IL-2 signal without a continuous TCR signal. ArticleCASPubMed 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. Blood108, 1571–1579 (2006). ArticleCASPubMedPubMed Central Google Scholar
Burchill, M. A. et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity28, 112–121 (2008). ArticleCASPubMedPubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature445, 771–775 (2007). ArticleCASPubMed Google Scholar
Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity27, 786–800 (2007). ArticleCASPubMed 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). ArticleCASPubMed 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). ArticleCAS 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. Immunity32, 642–653 (2010). ArticleCASPubMedPubMed 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). ArticlePubMed 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). ArticleCASPubMedPubMed Central Google Scholar
Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity22, 329–341 (2005). ArticleCASPubMed Google Scholar
Liston, A. et al. Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc. Natl Acad. Sci. USA105, 11903–11908 (2008). ArticleCASPubMedPubMed Central Google Scholar
Wan, Y. Y. & Flavell, R. A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl Acad. Sci. USA102, 5126–5131 (2005). ArticleCASPubMedPubMed 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. USA103, 8453–8458 (2006). ArticleCASPubMedPubMed 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). ArticleCASPubMed 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). ArticleCAS Google Scholar
Proietto, A. I. et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl Acad. Sci. USA105, 19869–19874 (2008). ArticleCASPubMedPubMed 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). ArticleCAS 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). ArticleCASPubMedPubMed Central 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. Nature455, 396–400 (2008). ArticleCASPubMed Google Scholar
Koble, C. & Kyewski, B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med.206, 1505–1513 (2009). ArticleCASPubMedPubMed 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). ArticleCASPubMed Google Scholar
Hubert, F. X. et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood118, 2462–2472 (2011). ArticleCASPubMed 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). ArticleCASPubMedPubMed 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). ArticleCASPubMed Google Scholar