Abstract
In the periphery, tolerance to self antigens is mainly mediated by the CD4+CD25+FOXP3+ subset of regulatory T cells, which can suppress the activity of autoreactive T cells that have escaped deletion in the thymus. The essential role of the transcription factor FOXP3 (forkhead box P3) in the development and function of these regulatory T cells has been well documented. It is also clear that regulatory T cells and effector T cells respond differently to T-cell receptor stimulation. In this Opinion article, we propose that these differences in responses are mediated by FOXP3, and are manifested by alterations in biochemical signalling pathways, patterns of gene expression and the appearance of cell-surface homing receptors.
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References
Shevach, E. M. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25, 195–201 (2006).
Shevach, E. M. et al. The lifestyle of naturally occurring CD4+CD25+Foxp3+ regulatory T cells. Immunol. Rev. 212, 60–73 (2006).
Bluestone, J. A. & Abbas, A. K. Natural versus adapted regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).
Fontenot, J. D. & Rudensky, A. Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nature Immunol. 6, 331–337 (2005).
Sakaguchi, S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458 (2000).
Shevach, E. M. Regulatory T cells in autoimmunity. Annu. Rev. Immunol. 18, 423–449 (2000).
Godfrey, V., Wilkinson, J. E. & Russell, L. B. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. Am. J. Pathol. 138, 1379–1387 (1991).
Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001).
Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutation of FOXP3. Nature Genet. 27, 20–21 (2001).
Gambineri, E., Torgerson, T. R. & Ochs, H. D. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T cell homeostasis. Curr. Opin. Rheumatol. 15, 430–435 (2003).
Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).
Torgerson, T. R. & Ochs, H. D. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a model of immune dysregulation. Curr. Opin. Allergy Clin. Immunol. 2, 481–487 (2002).
Chae, W.-J., Henegariu, O., Lee, S.-K. & Bothwell, A. L. M. The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells. Proc. Natl Acad. Sci. USA 103, 9631–9636 (2006).
Lopes, J. E. et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J. Immunol. 177, 3133–3142 (2006).
Wang, B., Lin, D., Li, C. & Tucker, P. W. Multiple domains define the expression and regulatory properties of Foxp1 forkhead transcriptional repressors. J. Biol. Chem. 278, 24259–24268 (2003).
Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).
Chen, C., Rowell, E. A., Thomas, R. M., Hancock, W. W. & Wells, A. D. Transcriptional regulation by FOXP3 is associated with direct promoter occupancy and modulation of histone acetylation. J. Biol. Chem. 281, 36828–36834 (2006).
Bettelli, E., Dastrange, M. & Oukka, M. Foxp3 interacts with nuclear factor of activated T cells and NF-κB to repress cytokine gene expression and effector functions of T helper cells. Proc. Natl Acad. Sci. USA 102, 5138–5143 (2005).
Li, B. et al. FOXP3 ensembles in T-cell regulation. Immunol. Rev. 212, 99–113 (2006).
Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007).
Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931–935 (2007).
Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).
Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
Lin, W. et al. Regulatory T cell development in the absence of functional Foxp3. Nature Immunol. 2 Feb 2007 (doi: 10.1038/ni1445).
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).
Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63 (2007).
Crabtree, G. R. & Clipstone, N. A. Signal transmission between the plasma membrane and the nucleus of T lymphocytes. Annu. Rev. Biochem. 63, 1045–1083 (1994).
Liu, J. O. The yins of T cell activation. Sci. STKE 265, re 1 (2005).
Laouar, Y. & Crispe, I. N. Functional flexibility in T cells: Independent regulation of CD4+ T cell proliferation and effector function in vivo. Immunity 13, 291–301 (2000).
Sechi, A. S. & Wehland, J. Interplay between TCR signaling and actin cytoskeleton dynamics. Trends Immunol. 25, 257–265 (2004).
Fuller, C. L., Braciale, V. L. & Samelson, L. E. All roads lead to actin: the intimate relationship between TCR signaling and the cytoskeleton. Immunol. Rev. 191, 220–236 (2003).
Baecher-Allan C., Brown, J. A., Freeman G. J. & Hafler, D. A. CD4+CD25high regulatory cells in human peripheral blood. J. Immunol. 167, 1245–1253 (2001).
Li, L. et al. CD4+CD25+ regulatory T-cell lines from human cord blood have functional and molecular properties of T-cell anergy. Blood 106, 3068–3073 (2005).
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).
Allan, S. E. et al. The role of FOXP3, and an isoform lacking exon 2, in the generation of human CD4+ T regulatory cells. J. Clin. Invest. 115, 3276–3284 (2005).
Baecher-Allan C., Viglietta, V. & Hafler, D. A. Human CD4+CD25+ regulatory T cells. Semin. Immunol. 16, 89–98 (2004).
Jonuleit, H. et al. Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285–1294 (2001).
Thornton, A. M. & Shevach, E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).
Gavin, M., Clarke, S. R., Negrou, E., Gallegos, A. & Rudensky, A. Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nature Immunol. 3, 33–41 (2002).
Carson, B. D. & Ziegler, S. F. Impaired T cell receptor signaling in Foxp3+ CD4 T cells. Ann. NY Acad. Sci. (in the press).
Hickman, S. P., Yang, J., Thomas, R. M., Wells, A. D. & Turka, L. A. Defective activation of protein kinase C and Ras–Erk pathways limits IL-2 production and proliferation by CD4+CD25+ regulatory T cells. J. Immunol. 177, 2186–2194 (2006).
Tsang, J. Y.-S. et al. Altered proximal T cell receptor (TCR) signaling in human CD4+CD25+ regulatory T cells. J. Leukoc. Biol. 80, 145–151 (2006).
Fuller, C. L., Braciale, V. L. & Samelson, L. E. All roads lead to actin: the intimate relationship between TCR signaling and the cytoskeleton. Immunol. Rev. 191, 220–236 (2003).
Clements, J. L., Boerth, N. J., Lee, J. R. & Koretzky, G. A. Integration of T cell receptor-dependent signaling pathways by adapter proteins. Annu. Rev. Immunol. 17, 89–108 (1999).
Miletic, A. V., Swat, M., Fujikawa, K. & Swat, W. Cytoskeletal remodeling in lymphocyte activation. Curr. Opin. Immunol. 15, 261–268 (2003).
Knoechel, B. et al. Functional and molecular comparison of anergic and regulatory T lymphocytes. J. Immunol. 176, 6473–6483 (2006).
Wang, J., Ioan-Facsinay, A., van der Voort, E. I. H., Huizinga, T. W. J. & Toes, R. E. M. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37, 129–138 (2007).
Morgan, M. E. et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum. Immunol. 66, 13–20 (2005).
Walker, M. R. et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25− T cells. J. Clin. Invest. 112, 1437–1443 (2003).
Gavin, M. A. et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl Acad. Sci. USA 103, 6659–6664 (2006).
Ziegler, S. F. FOXP3: Of mice and men. Annu. Rev. Immunol. 24, 209–226 (2006).
Ziegler, S. F. FOXP3: Not just for regulatory T cells any more. Eur. J. Immunol. 37, 21–23 (2007).
Kasprowicz, D. J., Smallwood, P. S., Tyznik, A. J. & Ziegler, S. F. Scurfin (FoxP3) controls T-dependent immune responses in vivo through regulation of CD4+ T cell effector function. J. Immunol. 171, 1216–1223 (2003).
Kasprowicz, D. J. et al. Dynamic regulation of FoxP3 expression controls the balance between CD4+ T cell activation and cell death. Eur. J. Immunol. 35, 3424–3432 (2005).
Khattri, R. et al. The amount of scurfin protein determines peripheral T cell number and responsiveness. J. Immunol. 167, 6312–6320 (2001).
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).
Murawski, M. R., Llitherland, S. A., Clare-Salzler, M. J. & Davoodi-Semiromi, A. Upregulation of Foxp3 expression in mouse and human Treg is IL-2/STAT5 dependent: implications for the NOD STAT5B mutation in diabetes pathogenesis. Ann. NY Acad. Sci. 1079, 198–204 (2006).
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).
Huehn, J. et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J. Exp. Med. 199, 303–313 (2004).
Lee, J. H., Kang, S. G. & Kim, C. H. FoxP3+ T cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues. J. Immunol. 178, 301–311 (2007).
Campbell, D. J., Kim, C. H. & Butcher, E. C. Separable effector T cell populations specialized for B cell help or tissue inflammation. Nature Immunol. 2, 876–881 (2001).
Kim, C. H. et al. Rules of chemokine receptor association with T cell polarization in vivo. J. Clin. Invest. 108, 1331–1339 (2001).
Lametschwandtner, G. et al. Sustained T-bet expression confers polarized human TH2 cells with TH1-like cytokine production and migratory capacities. J. Allergy Clin. Immunol. 113, 987–994 (2004).
Lord, G. M. et al. T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 106, 3432–3439 (2005).
Lehmann, J. et al. Expression of the integrin αEβ7 identifies unique subsets of CD25+ as well as CD25− regulatory T cells. Proc. Natl Acad. Sci. USA 99, 13031–13036 (2002).
Kleinewietfeld, M. et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105, 2877–2886 (2005).
Kunkel, E. J., Campbell, D. J. & Butcher, E. C. Chemokines in lymphocyte trafficking and intestinal immunity. Microcirculation 10, 313–323 (2003).
Dieu-Nosjean, M. C. et al. Macrophage inflammatory protein 3α is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J. Exp. Med. 192, 705–718 (2000).
Suffia, I., Reckling, S. K., Salay, G. & Belkaid, Y. A role for CD103 in the retention of CD4+CD25+ Treg and control of Leishmania major infection. J. Immunol. 174, 5444–5455 (2005).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor FoxP3. Science 299, 1057–1061 (2003).
Acknowledgements
We thank M. Warren for help in preparing this manuscript. Support for this work came in part from grants from the National Institutes of Health, USA (S.F.Z. and D.J.C.), the Juvenile Diabetes Research Foundation's Collaborative Center for Cellular Therapy (S.F.Z.) and the American Diabetes Association (S.F.Z.).
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Campbell, D., Ziegler, S. FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nat Rev Immunol 7, 305–310 (2007). https://doi.org/10.1038/nri2061
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DOI: https://doi.org/10.1038/nri2061
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