|FOXP3 Complex and Its Function in Regulatory T Cells
|KONG Chao1,2, LI Dan2, CHEN Zuojia2, PICCION Miranda2, YUAN Xiaojun1, LI Bin2
|1. Shanghai Key Laboratory of Bio-energy Crops, College of Life Science, Shanghai University, Shanghai 200444, China;
2. Key Laboratory of Molecular Virology & Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
Abstract: FOXP3+CD4+CD25+ regulatory T cells(FOXP3+Tregs)belong to a specific subset of CD4+ T cells which modulate many immune responses and play an indispensable role in maintaining immune homeostasis in vivo. Many major human diseases such as the autoimmune disease, the infectious disease, the allergic disease, the transplanting rejection and the cancers are associated with the dysfunction of the Tregs. The forkhead family transcription factor FOXP3 is a master regulator in the development and functions of the Tregs. Recently, a common conclusion is shared by many reseachers that the FOXP3 is not a solo transcription factor, it interacts with some other transcription factors such as the STAT3 and the RORγt to form a complex, to dynamically modulate the specific gene transcription progress. Furthermore, many studies including those of our laboratory demonstrate that posttranslational modification of the FOXP3 also plays an important role in the functions of the Tregs. In summary, further understanding of molecular mechanisms underlying the regulation of the FOXP3+Treg function by inflammation will lead a novel therapeutic clue for conquering major human diseases.
Received: 22 January 2014
|  Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance[J]. Cell, 2008, 133(5): 775-787.
 Li B, Greene M I. Special regulatory Tcell review: FOXP3 biochemistry in regulatory T cells—how diverse signals regulate suppression[J]. Immunology, 2008, 123(1): 17-19.
 Li B, Samanta A, Song X, et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression[J]. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104(11): 4571-4576.
 Li B, Samanta A, Song X, et al. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease[J]. International Immunology, 2007, 19(7): 825-835.
 Chen Z, Barbi J, Bu S, et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3[J]. Immunity, 2013, 39(2): 272-285.
 Littman D R, Rudensky A Y. Th17 and regulatory T cells in mediating and restraining inflammation[J]. Cell, 2010, 140(6): 845-858.
 Godfrey V L, Wilkinson J E, Russell L B. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse[J]. American Journal of Pathology, 1991, 138(6): 1379-1387.
 Bennett C L, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3[J]. Nature Genetics, 2001, 27(1): 20-21.
 Wildin R S, Freitas A. IPEX and FOXP3: Clinical and research perspectives[J]. Journal of Autoimmunity, 2005, 25(S): 56-62.
 Williams L M, Rudensky A Y. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3[J]. Nature Immunology, 2007, 8(3): 277-284.
 Rudra D, Deroos P, Chaudhry A, et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network[J]. Nature Immunology, 2012, 13(10): 1010-1019.
 Xiao Y, Li B, Zhou Z, et al. Histone acetyltransferase mediated regulation of FOXP3 acetylation and Treg function[J]. Current Opinion in Immunology, 2010, 22(5): 583-591.
 Chae W J, Henegariu O, Lee S K, et al. The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(25): 9631-9636.
 Song X, Li B, Xiao Y, et al. Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function[J]. Cell Reports, 2012, 1(6): 665-675.
 Ichiyama K, Yoshida H, Wakabayashi Y, et al. Foxp3 inhibits ROR gammatmediated IL17A mRNA transcription through direct interaction with ROR gammat[J]. Journal of Biological Chemistry, 2008, 283(25): 17003-17008.
 Du J, Huang C, Zhou B, et al. Isoform-specific inhibition of ROR alphamediated transcriptional activation by human FOXP3[J]. Journal of Immunology, 2008, 180(7): 4785-4792.
 Zheng Y, Chaudhry A, Kas A, et al. Regulatory Tcell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses[J]. Nature, 2009, 458(7236): 351-356.
 Koch M A, Tucker-Heard G, Perdue N R, et al. The transcription factor Tbet controls regulatory T cell homeostasis and function during type 1 inflammation[J]. Nature Immunology, 2009, 10(6): 595602.
 Chaudhry A, Rudra D, Treuting P, et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner[J]. Science, 2009, 326 (5955): 986-991.
 Pan F, Yu H, Dang E V, et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells[J]. Science, 2009, 325(5944): 11421146.
 Rooney J W, Sun Y L, Glimcher L H, et al. Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation[J]. Molecular and Cellular Biology, 1995, 15(11): 6299-6310.
 Macian F, LopezRodriguez C, Rao A. Partners in transcription: NFAT and AP-1[J]. Oncogene, 2001, 20(19): 2476-2489.
 Rao A, Luo C, Hogan P G. Transcription factors of the NFAT family: regulation and function[J]. Annual Review of Immunology, 1997, 15: 707-747.
 Wu Y, Borde M, Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT[J]. Cell, 2006, 126(2): 375-387.
 Zeng W P, Sollars V E, Belalcazar Adel P. Domain requirements for the diverse immune regulatory functions of Foxp3[J]. Molecular Immunology, 2011, 48(15-16): 1932-1939.
 Lee S M, Gao B, Fang D. FoxP3 maintains Treg unresponsiveness by selectively inhibiting the promoter DNA-binding activity of AP-1[J]. Blood, 2008, 111(7): 3599-3606.
 Haiqi H, Yong Z, Yi L. Transcriptional regulation of Foxp3 in regulatory T cells[J]. Immunobiology, 2011, 216(6): 678-685.
 Klunker S, Chong M M, Mantel P Y, et al. Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3 + inducible regulatory T cells[J]. Journal of Experimental Medicine, 2009, 206(12): 2701-2715.
 Xu L, Kitani A, Stuelten C, et al. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I[J]. Immunity, 2010, 33(3): 313-325.
 Mantel P Y, Kuipers H, Boyman O, et al. GATA3driven Th2 responses inhibit TGFbeta1induced FOXP3 expression and the formation of regulatory T cells[J]. PLoS Biology, 2007, 5(12): e329.
 Wang Y, Su M A, Wan Y Y. An essential role of the transcription factor GATA3 for the function of regulatory T cells[J]. Immunity, 2011, 35(3): 337-348.
 Samstein R M, Arvey A, Josefowicz S Z, et al. Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification[J]. Cell, 2012, 151(1): 153-166.
 Van Loosdregt J, Vercoulen Y, Guichelaar T, et al. Regulation of Treg functionality by acetylationmediated Foxp3 protein stabilization[J]. Blood, 2010, 115(5): 965-974.
 Van Loosdregt J, Fleskens V, Fu J, et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Tregcellsuppressive capacity[J]. Immunity, 2013, 39(2): 259-271.
 Shi L Z, Wang R, Huang G, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells[J]. Journal of Experimental Medicine, 2011, 208 (7): 1367-1376.
 Dang E V, Barbi J, Yang H Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1[J]. Cell, 2011, 146(5): 772-784.
 Brunkow M E, Jeffery E W, Hjerrild K A, et al. Disruption of a new forkhead/wingedhelix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse[J]. Nature Genetics, 2001, 27(1): 68-73.
 Rudensky A Y, Campbell D J. In vivo sites and cellular mechanisms of T reg cell-mediated suppression[J]. Journal Experimental Medicine, 2006, 203(3): 489-492.
 Lehtimaki S, Lahesmaa R. Regulatory T cells control immune responses through their nonredundant tissue specific features[J]. Frontiers in Immunology, 2013, 4: 294.
 Belkaid Y, Tarbell K. Regulatory T cells in the control of hostmicroorganism interactions (*) [J]. Annual Review of Immunology, 2009, 27: 551-589.
 Han D, Walsh M C, Cejas P J, et al. Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiotadependent immune tolerance[J]. Immunity, 2013, 38(6): 1211-1222.
 Mason D, Powrie F. Control of immune pathology by regulatory T cells[J]. Current Opinion in Immunology, 1998, 10(6): 649-655.
 Powrie F, Leach M W, Mauze S, et al. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice[J]. International Immunology, 1993, 5(11): 14611471.
 Aida K, Miyakawa R, Suzuki K, et al. Suppression of Tregs by antiglucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferonalpha gene therapy for pancreatic cancer[J]. Cancer Science, 2013.
 Darce J, Rudra D, Li L, et al. An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes[J]. Immunity, 2012, 36(5): 731-741.
 Bettini M L, Pan F, Bettini M, et al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency[J]. Immunity, 2012, 36(5): 717-730.
 Pandiyan P, Zheng L, Ishihara S, et al. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivationmediated apoptosis of effector CD4+ T cells[J]. Nature Immunology, 2007, 8(12): 1353-1362.
 Wu H, Li P, Shao N, et al. Aberrant expression of Treg-associated cytokine IL35 along with IL10 and TGFbeta in acute myeloid leukemia[J]. Oncology Letter, 2012, 3(5): 1119-1123.
 Collison L W, Workman C J, Kuo T T, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function[J]. Nature, 2007, 450 (7169): 566-569.
 Garin M I, Chu C C, Golshayan D, et al. Galectin-1: A key effector of regulation mediated by CD4+ CD25+ T cells[J]. Blood, 2007, 109(5): 2058-2065.
 Onishi Y, Fehervari Z, Yamaguchi T, et al. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation[J]. Proceedings of National Academy of Sciences of the United States of America, 2008, 105(29): 1011310118.
 Shevach E M. Mechanisms of Foxp3+ T regulatory cell-mediated suppression[J]. Immunity, 2009, 30(5): 636-645.
 Delgoffe G M, Woo S R, Turnis M E, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis[J]. Nature, 2013, 501(7466): 252-256.
 Gershon R K, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes[J]. Immunology, 1970, 18(5): 723-737.
 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 Tcell homeostasis[J]. Current Opinion in Rheumatology, 2003, 15(4): 430-435.
 Wildin R S, Smyk-Pearson S, Filipovich A H. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome[J]. Journal of Medical Genetics, 2002, 39 (8): 537-545.
 Gambineri E, Perroni L, Passerini L, et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, Xlinked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity[J]. Journal of Allergy and Clinical Immunology, 2008, 122 (6): 1105-1112 e1101.
 Lampasona V, Passerini L, Barzaghi F, et al. Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syndrome[J]. PLoS One, 2013, 8(11): e78664.
 Dunn G P, Old L J, Schreiber R D. The immunobiology of cancer immunosurveillance and immunoediting[J]. Immunity, 2004, 21(2): 137-148.
 Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance[J]. Nature Reviews Cancer, 2005, 5(4): 263-274.
 Zou W. Regulatory T cells, tumour immunity and immunotherapy[J]. Nature Reviews Immunology, 2006, 6(4): 295-307.
 Curiel T J, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival[J]. Nature Medicine, 2004, 10(9): 942-949.
 Govindaraj C, Tan P, Walker P, et al. Reducing TNF Receptor 2+ regulatory T cells via the combined action of azacitidine and the HDAC inhibitor panobinostat for clinical benefit in acute myeloid leukemia patients[J]. Clinical Cancer Reserch, 2013.
 Martin-Orozco N, Li Y, Wang Y, et al. Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells[J]. Cancer Reserch, 2010, 70(23): 9581-9590.
 Sim G C, MartinOrozco N, Jin L, et al. IL2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients[J]. Journal of Clinical Investigation, 2013.
 Sugimoto K, Ikeda F, Stadanlick J, et al. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection[J]. Hepatology, 2003, 38(6): 1437-1448.
 Park S H, Veerapu N S, Shin E C, et al. Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection[J]. Nature Medicine, 2013, 19(12): 1638-1642.
 Kinter A L, Hennessey M, Bell A, et al. CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIVinfected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status[J]. Journal of Experimental Medicine, 2004, 200(3): 331-343.
 Singh A, Vajpayee M, Ali S A, et al. Cellular interplay among Th17, Th1, and Treg cells in HIV1 subtype "C" infection[J]. Journal of Medical Virology, 2013.