- About this Journal
- Abstracting and Indexing
- Aims and Scope
- Annual Issues
- Article Processing Charges
- Articles in Press
- Author Guidelines
- Bibliographic Information
- Citations to this Journal
- Contact Information
- Editorial Board
- Editorial Workflow
- Free eTOC Alerts
- Publication Ethics
- Reviewers Acknowledgment
- Submit a Manuscript
- Subscription Information
- Table of Contents
Clinical and Developmental Immunology
Volume 2013 (2013), Article ID 617595, 8 pages
Thymic Regulatory T Cell Development: Role of Signalling Pathways and Transcription Factors
1Centre for Inflammatory Diseases, Monash Medical Centre, Southern Clinical School, Monash University, Clayton, VIC 3168, Australia
2Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
3Department of Clinical Haematology, Central Clinical School, Melbourne, VIC 3000, Australia
Received 14 June 2013; Accepted 21 August 2013
Academic Editor: E. Shevach
Copyright © 2013 Mark Engel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- L. Klein, M. Hinterberger, G. Wirnsberger, and B. Kyewski, “Antigen presentation in the thymus for positive selection and central tolerance induction,” Nature Reviews Immunology, vol. 9, no. 12, pp. 833–844, 2009.
- M. S. Anderson and M. A. Su, “Aire and T cell development,” Current Opinion in Immunology, vol. 23, no. 2, pp. 198–206, 2011.
- A. D. Griesemer, E. C. Sorenson, and M. A. Hardy, “The role of the thymus in tolerance,” Transplantation, vol. 90, no. 5, pp. 465–474, 2010.
- S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, and M. Toda, “Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases,” Journal of Immunology, vol. 155, no. 3, pp. 1151–1164, 1995.
- S. Sakaguchi, T. Yamaguchi, T. Nomura, and M. Ono, “Regulatory T cells and immune tolerance,” Cell, vol. 133, no. 5, pp. 775–787, 2008.
- S. Sakaguchi, K. Fukuma, K. Kuribayashi, and T. Masuda, “Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participiation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease,” Journal of Experimental Medicine, vol. 161, no. 1, pp. 72–87, 1985.
- S. Hori, T. Nomura, and S. Sakaguchi, “Control of regulatory T cell development by the transcription factor Foxp3,” Science, vol. 299, no. 5609, pp. 1057–1061, 2003.
- J. D. Fontenot, M. A. Gavin, and A. Y. Rudensky, “Foxp3 programs the development and function of CD4+CD25+ regulatory T cells,” Nature Immunology, vol. 4, no. 4, pp. 330–336, 2003.
- R. Khattri, T. Cox, S. A. Yasayko, and F. Ramsdell, “An essential role for Scurfin in CD4+CD25+ T regulatory cells,” Nature Immunology, vol. 4, no. 4, pp. 337–342, 2003.
- J. D. Fontenot, J. L. Dooley, A. G. Farr, and A. Y. Rudensky, “Developmental regulation of Foxp3 expression during ontogeny,” Journal of Experimental Medicine, vol. 202, no. 7, pp. 901–906, 2005.
- E. M. Shevach, T. S. Davidson, E. N. Huter, R. A. DiPaolo, and J. Andersson, “Role of TGF-β in the induction of Foxp3 expression and T regulatory cell function,” Journal of Clinical Immunology, vol. 28, no. 6, pp. 640–646, 2008.
- I. Apostolou, A. Sarukhan, L. Klein, and H. von Boehmer, “Origin of regulatory T cells with known specificity for antigen,” Nature Immunology, vol. 3, no. 8, pp. 756–763, 2002.
- M. S. Jordan, A. Boesteanu, A. J. Reed et al., “Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide,” Nature Immunology, vol. 2, no. 4, pp. 301–306, 2001.
- M. A. Lerman, J. Larkin III, C. Cozzo, M. S. Jordan, and A. J. Caton, “CD4+ CD25+ regulatory T cell repertoire formation in response to varying expression of a neo-self-antigen,” Journal of Immunology, vol. 173, no. 1, pp. 236–244, 2004.
- J. Cabarrocas, C. Cassan, F. Magnusson et al., “Foxp3+ CD25+ regulatory T cells specific for a neo-self-antigen develop at the double-positive thymic stage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 22, pp. 8453–8458, 2006.
- C. W. J. Lio and C. S. Hsieh, “A two-step process for thymic regulatory T cell development,” Immunity, vol. 28, no. 1, pp. 100–111, 2008.
- C. W. J. Lio, L. F. Dodson, C. M. Deppong, C. S. Hsieh, and J. M. Green, “CD28 facilitates the generation of Foxp3-cytokine responsive regulatory T cell precursors,” Journal of Immunology, vol. 184, no. 11, pp. 6007–6013, 2010.
- K. B. Vang, J. Yang, A. J. Pagán et al., “Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoir,” Journal of Immunology, vol. 184, no. 8, pp. 4074–4077, 2010.
- M. A. Burchill, J. Yang, K. B. Vang et al., “Linked T Cell Receptor and Cytokine Signaling Govern the Development of the Regulatory T Cell Repertoire,” Immunity, vol. 28, no. 1, pp. 112–121, 2008.
- S. Gerondakis, A. Banerjee, G. Grigoriadis et al., “NF-κB subunit specificity in hemopoiesis,” Immunological Reviews, vol. 246, no. 1, pp. 272–285, 2012.
- F. Macian, “NFAT proteins: key regulators of T-cell development and function,” Nature Reviews Immunology, vol. 5, no. 6, pp. 472–484, 2005.
- P. G. Hogan, L. Chen, J. Nardone, and A. Rao, “Transcriptional regulation by calcium, calcineurin, and NFAT,” Genes and Development, vol. 17, no. 18, pp. 2205–2232, 2003.
- S. Gupta, S. Manicassamy, C. Vasu, A. Kumar, W. Shang, and Z. Sun, “Differential requirement of PKC-θ in the development and function of natural regulatory T cells,” Molecular Immunology, vol. 46, no. 2, pp. 213–224, 2008.
- Y. Wu, M. Borde, V. Heissmeyer et al., “FOXP3 controls regulatory T cell function through cooperation with NFAT,” Cell, vol. 126, no. 2, pp. 375–387, 2006.
- R. Zeiser, V. H. Nguyen, A. Beilhack et al., “Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production,” Blood, vol. 108, no. 1, pp. 390–399, 2006.
- Y. Tone, K. Furuuchi, Y. Kojima, M. L. Tykocinski, M. I. Greene, and M. Tone, “Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer,” Nature Immunology, vol. 9, no. 2, pp. 194–202, 2008.
- M. Vaeth, U. Schliesser, G. Muller et al., “Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 40, pp. 16258–16263, 2012.
- M. Oh-hora and A. rao, “The calcium/NFAT pathway: role in development and function of regulatory T cells,” Microbes and Infection, vol. 11, no. 5, pp. 612–619, 2009.
- T. Bopp, A. Palmetshofer, E. Serfling et al., “NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells,” Journal of Experimental Medicine, vol. 201, no. 2, pp. 181–187, 2005.
- O. F. Bueno, E. B. Brandt, M. E. Rothenberg, and J. D. Molkentin, “Defective T cell development and function in calcineurin Aβ-deficient mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 14, pp. 9398–9403, 2002.
- E. M. Gallo, M. M. Winslow, K. Canté-Barrett et al., “Calcineurin sets the bandwidth for discrimination of signals during thymocyte development,” Nature, vol. 450, no. 7170, pp. 731–735, 2007.
- J. R. Neilson, M. M. Winslow, E. M. Hur, and G. R. Crabtree, “Calcineurin B1 is essential for positive but not negative selection during thymocyte development,” Immunity, vol. 20, no. 3, pp. 255–266, 2004.
- Q. Li, A. Shakya, X. Guo et al., “Constitutive nuclear localization of NFAT in Foxp3+ regulatory T cells independent of calcineurin activity,” Journal of Immunology, vol. 188, no. 9, pp. 4268–4277, 2012.
- B. D. Medoff, B. P. Sandall, A. Landry et al., “Differential requirement for CARMA1 in agonist-selected T-cell development,” European Journal of Immunology, vol. 39, no. 1, pp. 78–84, 2009.
- L. L. Molinero, J. Yang, T. Gajewski, C. Abraham, M. A. Farrar, and M. L. Alegre, “CARMA1 controls an early checkpoint in the thymic development of foxP3 + regulatory T cells,” Journal of Immunology, vol. 182, no. 11, pp. 6736–6743, 2009.
- M. Schmidt-Supprian, G. Courtois, J. Tian et al., “Mature T cells depend on signaling through the IKK complex,” Immunity, vol. 19, no. 3, pp. 377–389, 2003.
- M. Schmidt-Supprian, J. Tian, E. P. Grant et al., “Differential dependence of CD4+CD25+ regulatory and natural killer-like T cells on signals leading to NF-κB activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 13, pp. 4566–4571, 2004.
- O. Gaide, B. Favier, D. F. Legler et al., “CARMAI is a critical lipid raft-associated regulator of TCR-induced NF-κB activation,” Nature Immunology, vol. 3, no. 9, pp. 836–843, 2002.
- C. Jiang and X. Lin, “Regulation of NF-kappaB by the CARD proteins,” Immunological Reviews, vol. 246, no. 1, pp. 141–153, 2012.
- D. Wang, Y. You, S. M. Case et al., “A requirement for CARMAI in TCR-induced NF-κB activation,” Nature Immunology, vol. 3, no. 9, pp. 830–835, 2002.
- X. Lin and D. Wang, “The roles of CARMA1, Bcl10, and MALT1 in antigen receptor signaling,” Seminars in Immunology, vol. 16, no. 6, pp. 429–435, 2004.
- K. Sommer, B. Guo, J. L. Pomerantz et al., “Phosphorylation of the CARMA1 linker controls NF-κB activation,” Immunity, vol. 23, no. 6, pp. 561–574, 2005.
- D. Wang, R. Matsumoto, Y. You et al., “CD3/CD28 costimulation-induced NF-κB activation is mediated by recruitment of protein kinase C-θ, Bcl10, and IκB kinase β to the immunological synapse through CARMA1,” Molecular and Cellular Biology, vol. 24, no. 1, pp. 164–171, 2004.
- A. Hoffmann, G. Natoli, and G. Ghosh, “Transcriptional regulation via the NF-κB signaling module,” Oncogene, vol. 25, no. 51, pp. 6706–6716, 2006.
- C. Scheidereit, “IκB kinase complexes: gateways to NF-κB activation and transcription,” Oncogene, vol. 25, no. 51, pp. 6685–6705, 2006.
- H. Oh and S. Ghosh, “NF-κB: roles and regulation in different CD4(+) T-cell subsets,” Immunological Reviews, vol. 252, no. 1, pp. 41–51, 2013.
- I. Isomura, S. Palmer, R. J. Grumont et al., “c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells,” Journal of Experimental Medicine, vol. 206, no. 13, pp. 3001–3014, 2009.
- M. Long, S. G. Park, I. Strickland, M. S. Hayden, and S. Ghosh, “Nuclear factor-κB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor,” Immunity, vol. 31, no. 6, pp. 921–931, 2009.
- Q. Ruan, V. Kameswaran, Y. Tone et al., “Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome,” Immunity, vol. 31, no. 6, pp. 932–940, 2009.
- Y. Zheng, S. Josefowicz, A. Chaudhry, X. P. Peng, K. Forbush, and A. Y. Rudensky, “Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate,” Nature, vol. 463, no. 7282, pp. 808–812, 2010.
- E. K. Deenick, A. R. Elford, M. Pellegrini, H. Hall, T. W. Mak, and P. S. Ohashi, “c-Rel but not NF-κB1 is important for T regulatory cell development,” European Journal of Immunology, vol. 40, no. 3, pp. 677–681, 2010.
- G. Grigoriadis, A. Vasanthakumar, A. Banerjee et al., “C-rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells,” PLoS ONE, vol. 6, no. 10, Article ID e26851, 2011.
- A. J. Lee, X. Wu, H. Cheng, X. Zhou, X. Cheng, and S. C. Sun, “CARMA1 regulation of regulatory T cell development involves modulation of interleukin-2 receptor signaling,” Journal of Biological Chemistry, vol. 285, no. 21, pp. 15696–15703, 2010.
- S. Rao, S. Gerondakis, D. Woltring, and M. F. Shannon, “c-Rel is required for chromatin remodeling across the IL-2 gene promoter,” Journal of Immunology, vol. 170, no. 7, pp. 3724–3731, 2003.
- X. Tai, M. Cowan, L. Feigenbaum, and A. Singer, “CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2,” Nature Immunology, vol. 6, no. 2, pp. 152–162, 2005.
- H. Bour-Jordan and J. A. Bluestone, “Regulating the regulators: costimulatory signals control the homeostasis and function of regulatory T cells,” Immunological Reviews, vol. 229, no. 1, pp. 41–66, 2009.
- B. Salomon, D. J. Lenschow, L. Rhee et al., “B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes,” Immunity, vol. 12, no. 4, pp. 431–440, 2000.
- Q. Tang, K. J. Henriksen, E. K. Boden et al., “Cutting edge: CD28 controls peripheral homeostasis of CD4 +CD25+ regulatory T cells,” Journal of Immunology, vol. 171, no. 7, pp. 3348–3352, 2003.
- L. H. Boise, A. J. Minn, P. J. Noel et al., “CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-x(L),” Immunity, vol. 3, no. 1, pp. 87–98, 1995.
- J. S. Burr, N. D. L. Savage, G. E. Messah et al., “Cutting edge: distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL,” Journal of Immunology, vol. 166, no. 9, pp. 5331–5335, 2001.
- R. M. Thomas, L. Gao, and A. D. Wells, “Signals from CD28 induce stable epigenetic modification of the IL-2 promoter,” Journal of Immunology, vol. 174, no. 8, pp. 4639–4646, 2005.
- C. Nazarov-Stoica, J. Surls, C. Bona, S. Casares, and T. D. Brumeanu, “CD28 signaling in T regulatory precursors requires p56lck and rafts integrity to stabilize the Foxp3 message,” Journal of Immunology, vol. 182, no. 1, pp. 102–110, 2009.
- J. D. Fontenot, J. P. Rasmussen, M. A. Gavin, and A. Y. Rudensky, “A function for interleukin 2 in Foxp3-expressing regulatory T cells,” Nature Immunology, vol. 6, no. 11, pp. 1142–1151, 2005.
- L. M. D'Cruz and L. Klein, “Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling,” Nature Immunology, vol. 6, no. 11, pp. 1152–1159, 2005.
- C. L. Bennett, J. Christie, F. Ramsdell et al., “The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3,” Nature Genetics, vol. 27, no. 1, pp. 20–21, 2001.
- B. R. Powell, N. R. M. Buist, and P. Stenzel, “An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy,” Journal of Pediatrics, vol. 100, no. 5, pp. 731–737, 1982.
- R. S. Wildin, F. Ramsdell, J. Peake et al., “X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy,” Nature Genetics, vol. 27, no. 1, pp. 18–20, 2001.
- M. E. Brunkow, E. W. Jeffery, K. A. Hjerrild et al., “Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse,” Nature Genetics, vol. 27, no. 1, pp. 68–73, 2001.
- V. L. Godfrey, J. E. Wilkinson, and L. B. Russell, “X-linked lymphoreticular disease in the scurfy (sf) mutant mouse,” American Journal of Pathology, vol. 138, no. 6, pp. 1379–1387, 1991.
- H. P. Kim and W. J. Leonard, “CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation,” Journal of Experimental Medicine, vol. 204, no. 7, pp. 1543–1551, 2007.
- Z. Yao, Y. Kanno, M. Kerenyi et al., “Nonredundant roles for Stat5a/b in directly regulating Foxp,” Blood, vol. 109, no. 10, pp. 4368–4375, 2007.
- E. Zorn, E. A. Nelson, M. Mohseni 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, vol. 108, no. 5, pp. 1571–1579, 2006.
- M. A. Burchill, J. Yang, C. Vogtenhuber, B. R. Blazar, and M. A. Farrar, “IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells,” Journal of Immunology, vol. 178, no. 1, pp. 280–290, 2007.
- G. Lal, N. Zhang, W. Van Der Touw et al., “Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation,” Journal of Immunology, vol. 182, no. 1, pp. 259–273, 2009.
- S. Floess, J. Freyer, C. Siewert et al., “Epigenetic control of the foxp3 locus in regulatory T cells,” PLoS Biology, vol. 5, no. 2, article e38, 2007.
- A. Toker and J. Huehn, “To be or not to be a Treg cell: lineage decisions controlled by epigenetic mechanisms,” Science Signaling, vol. 4, no. 158, article pe4, 2011.
- B. Liu, S. Tahk, K. M. Yee, G. Fan, and K. Shuai, “The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression,” Science, vol. 330, no. 6003, pp. 521–525, 2010.
- W. Ouyang, O. Beckett, Q. Ma, J. H. Paik, R. A. Depinho, and M. O. Li, “Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells,” Nature Immunology, vol. 11, no. 7, pp. 618–627, 2010.
- L. F. Lu, T. H. Thai, D. P. Calado et al., “Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein,” Immunity, vol. 30, no. 1, pp. 80–91, 2009.
- S. Kohlhaas, O. A. Garden, C. Scudamore, M. Turner, K. Okkenhaug, and E. Vigorito, “Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells1,” Journal of Immunology, vol. 182, no. 5, pp. 2578–2582, 2009.