Abstract
Regulatory T cells (Treg cells) are required for peripheral tolerance. Evidence indicates that Treg cells can adopt specialized differentiation programs in the periphery that are controlled by transcription factors usually associated with helper T cell differentiation. Here we demonstrate that expression of the transcription factor Blimp-1 defined a population of Treg cells that localized mainly to mucosal sites and produced IL-10. Blimp-1 was required for IL-10 production by these cells and for their tissue homeostasis. We provide evidence that the transcription factor IRF4, but not the transcription factor T-bet, was essential for Blimp-1 expression and for the differentiation of all effector Treg cells. Thus, our study defines a differentiation pathway that leads to the acquisition of Treg cell effector functions and requires both IRF4 and Blimp-1.
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References
Lu, L.F. & Rudensky, A. Molecular orchestration of differentiation and function of regulatory T cells. Genes Dev. 23, 1270–1282 (2009).
Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
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).
Fontenot, J.D., Rasmussen, J.P., Gavin, M.A. & Rudensky, A.Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142–1151 (2005).
Zheng, Y. & Rudensky, A.Y. Foxp3 in control of the regulatory T cell lineage. Nat. Immunol. 8, 457–462 (2007).
Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).
Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).
Friedline, R.H. et al. CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J. Exp. Med. 206, 421–434 (2009).
Pandiyan, P., Zheng, L., Ishihara, S., Reed, J. & Lenardo, M.J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 8, 1353–1362 (2007).
Rubtsov, Y.P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).
Ito, T. et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 28, 870–880 (2008).
Kleinewietfeld, M. et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105, 2877–2886 (2005).
Strauss, L. et al. Expression of ICOS on human melanoma-infiltrating CD4+CD25highFoxp3+ T regulatory cells: implications and impact on tumor-mediated immune suppression. J. Immunol. 180, 2967–2980 (2008).
Zhang, N. et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity 30, 458–469 (2009).
Kamanaka, M. et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25, 941–952 (2006).
Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458, 351–356 (2009).
Koch, M.A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).
Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).
Gavin, M.A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007).
Nutt, S.L., Fairfax, K.A. & Kallies, A. BLIMP1 guides the fate of effector B and T cells. Nat. Rev. Immunol. 7, 923–927 (2007).
Kallies, A. & Nutt, S.L. Terminal differentiation of lymphocytes depends on Blimp-1. Curr. Opin. Immunol. 19, 156–162 (2007).
Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008).
Kallies, A. et al. Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat. Immunol. 7, 466–474 (2006).
Martins, G.A. et al. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7, 457–465 (2006).
Gong, D. & Malek, T.R. Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production. J. Immunol. 178, 242–252 (2007).
Santer-Nanan, B. et al. Blimp-1 is expressed in human and mouse T cell subsets and leads to loss of IL-2 production and to defective proliferation. Signal Transduct. 6, 268–279 (2006).
Cimmino, L. et al. Blimp-1 attenuates Th1 differentiation by repression of ifng, tbx21, and bcl6 gene expression. J. Immunol. 181, 2338–2347 (2008).
Johnston, R.J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).
Kallies, A., Xin, A., Belz, G.T. & Nutt, S.L. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity 31, 283–295 (2009).
Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).
Kallies, A. et al. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J. Exp. Med. 200, 967–977 (2004).
Mottet, C., Uhlig, H.H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).
Boyman, O., Kovar, M., Rubinstein, M.P., Surh, C.D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927 (2006).
Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).
Kwon, H. et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31, 941–952 (2009).
Mittrucker, H.W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540–543 (1997).
Brustle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nat. Immunol. 8, 958–966 (2007).
Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).
Shaffer, A.L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51–62 (2002).
Magnusdottir, E. et al. Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1. Proc. Natl. Acad. Sci. USA 104, 14988–14993 (2007).
Lee, C.G. et al. A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells. Mol. Immunol. 46, 613–621 (2009).
Ahyi, A.N., Chang, H.C., Dent, A.L., Nutt, S.L. & Kaplan, M.H. IFN regulatory factor 4 regulates the expression of a subset of Th2 cytokines. J. Immunol. 183, 1598–1606 (2009).
Campbell, D.J. & Koch, M.A. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat. Rev. Immunol. 11, 119–130 (2011).
Yamazaki, T. et al. CCR6 regulates the migration of inflammatory and regulatory T cells. J. Immunol. 181, 8391–8401 (2008).
Kitamura, K., Farber, J.M. & Kelsall, B.L. CCR6 marks regulatory T cells as a colon-tropic, IL-10-producing phenotype. J. Immunol. 185, 3295–3304 (2010).
Klein, U. et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7, 773–782 (2006).
Malissen, M. et al. Altered T cell development in mice with a targeted mutation of the CD3-epsilon gene. EMBO J. 14, 4641–4653 (1995).
Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).
Szabo, S.J. et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002).
Kallies, A. et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity 26, 555–566 (2007).
de Boer, E. et al. Efficient biotinylation and single-step purification of tagged transcription factors in mammalian cells and transgenic mice. Proc. Natl. Acad. Sci. USA 100, 7480–7485 (2003).
Driegen, S. et al. A generic tool for biotinylation of tagged proteins in transgenic mice. Transgenic Res. 14, 477–482 (2005).
Boyer, L.A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).
Ebert, A. et al. Novel regulatory elements with Pax5-dependent activity in pro-B cells are interspersed in the distal VH gene cluster of the Igh locus. Immunity (in the press).
Decker, T. et al. Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis. Immunity 30, 508–520 (2009).
Flynn, K.J. et al. Virus-specific CD8+ T cells in primary and secondary influenza pneumonia. Immunity 8, 683–691 (1998).
Shi, W., Oshlack, A. & Smyth, G.K . Optimizing the noise versus bias trade-off for Illumina Whole Genome Expression BeadChips. Nucleic Acids Res. (in the press).
Smyth, G.K. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, article 3 (2004).
Gentleman, R.C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).
Wu, D. et al. ROAST: rotation gene set tests for complex microarray experiments. Bioinformatics 26, 2176–2182 (2010).
Kel, A.E. et al. MATCH: A tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res. 31, 3576–3579 (2003).
Jeanmougin, F. et al. Multiple sequence alignment with Clustal X. Trends Biochem. Sci. 23, 403–405 (1998).
Acknowledgements
We thank T. Mak, L. Wu, J. Altin and P. Bouillet for mice; S. Sterle, N. Bernard, R. Thong and K. Elder for technical support; Y. Zhan, I. Campbell and K. Shortman for antibodies; L. Corcoran and D. Tarlinton for discussion and reagents; and Y. Zheng and A. Rudensky for the full microarray data set already published in part17. Supported by the National Health and Medical Research Council of Australia (E.C., G.T.B., S.L.N. and A.K.), L'Oréal Australia For Women in Science Fellowship (E.C.), the Swiss National Science Foundation (F.M.), the Viertel Foundation, the Howard Hughes Medical Institute (G.T.B.), the Pfizer Australia Research Fellowship program (S.L.N.), the Leukemia & Lymphoma Society (A.K.), Boehringer Ingelheim (Busslinger group) and the European Union Sixth Framework Programme FP6 (EuTRACC project, Busslinger group).
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E.C., A.X., M.M., F.M., M.M. and A.K. designed and did experiments; W.S. and G.K.S. analyzed the microarray data; G.T.B. and M.B. designed experiments; and S.L.N. and A.K. designed experiments and wrote the paper and contributed equally to this work.
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Cretney, E., Xin, A., Shi, W. et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12, 304–311 (2011). https://doi.org/10.1038/ni.2006
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DOI: https://doi.org/10.1038/ni.2006
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