Abstract
Forkhead box protein 3-expressing (FOXP3+) regulatory T cells (Treg cells) suppress conventional T cells and are essential for immunological tolerance. FOXP3, the master transcription factor of Treg cells, controls the expression of multiples genes to guide Treg cell differentiation and function. However, only a small fraction (<10%) of Treg cell-associated genes are directly bound by FOXP3, and FOXP3 alone is insufficient to fully specify the Treg cell programme, indicating a role for other accessory transcription factors operating upstream, downstream and/or concurrently with FOXP3 to direct Treg cell specification and specialized functions. Indeed, the heterogeneity of Treg cells can be at least partially attributed to differential expression of transcription factors that fine-tune their trafficking, survival and functional properties, some of which are niche-specific. In this Review, we discuss the emerging roles of accessory transcription factors in controlling Treg cell identity. We specifically focus on members of the basic helix–loop–helix family (AHR), basic leucine zipper family (BACH2, NFIL3 and BATF), CUT homeobox family (SATB1), zinc-finger domain family (BLIMP1, Ikaros and BCL-11B) and interferon regulatory factor family (IRF4), as well as lineage-defining transcription factors (T-bet, GATA3, RORγt and BCL-6). Understanding the imprinting of Treg cell identity and specialized function will be key to unravelling basic mechanisms of autoimmunity and identifying novel targets for drug development.
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References
Sakaguchi, S., Fukuma, K., Kuribayashi, K. & Masuda, T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161, 72–87 (1985).
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). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
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).
Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).
Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).
Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).
Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007).
Sugimoto, N. et al. Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int. Immunol. 18, 1197–1209 (2006).
Birzele, F. et al. Next-generation insights into regulatory T cells: expression profiling and FoxP3 occupancy in human. Nucleic Acids Res. 39, 7946–7960 (2011).
Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936–940 (2007). Together with Birzele et al. (2011), this work shows that FOXP3-bound genes represent only a small fraction of the hallmark Treg cell genes that are directly regulated by FOXP3.
O’Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 1098–1102 (2010).
Hirahara, K. et al. Helper T-cell differentiation and plasticity: insights from epigenetics. Immunology 134, 235–245 (2011).
Nakayamada, S., Takahashi, H., Kanno, Y. & O’Shea, J. J. Helper T cell diversity and plasticity. Curr. Opin. Immunol. 24, 297–302 (2012).
Kumar, D., Sahoo, S. S., Chauss, D., Kazemian, M. & Afzali, B. Non-coding RNAs in immunoregulation and autoimmunity: technological advances and critical limitations. J. Autoimmun. 134, 102982 (2023).
Sharabi, A. et al. Regulatory T cells in the treatment of disease. Nat. Rev. Drug Discov. 17, 823–844 (2018).
Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).
Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100–111 (2008).
Baron, U. et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells. Eur. J. Immunol. 37, 2378–2389 (2007).
Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).
Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749–763 (2014).
Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010).
Toker, A. et al. Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J. Immunol. 190, 3180–3188 (2013).
Vignali, D. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).
Akkaya, B. et al. Regulatory T cells mediate specific suppression by depleting peptide–MHC class II from dendritic cells. Nat. Immunol. 20, 218–231 (2019).
Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785–799 (2012).
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).
Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368–4375 (2007).
Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).
Camperio, C. et al. Forkhead transcription factor FOXP3 upregulates CD25 expression through cooperation with RelA/NF-κB. PLoS ONE 7, e48303 (2012).
Ono, M. et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685–689 (2007).
Kim, H. P. & Leonard, W. J. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 204, 1543–1551 (2007).
Takimoto, T. et al. Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and TH1 development. J. Immunol. 185, 842–855 (2010).
Wong, W. F. et al. Runx1 deficiency in CD4+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells. J. Immunol. 188, 5408–5420 (2012).
Helms, C. et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat. Genet. 35, 349–356 (2003).
Cretney, E. 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). This publication shows that BLIMP1 and IRF4 cooperate to define a subset of specialized IL-10−-producing Treg cells within the mucosal tissues.
Vasanthakumar, A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015). This study provides evidence that IL-33 drives the expression of IRF4 and BATF, which are essential for functional maintenance of visceral adipose tissue Treg cells.
Bhairavabhotla, R. et al. Transcriptome profiling of human FoxP3+ regulatory T cells. Hum. Immunol. 77, 201–213 (2016).
Zemmour, D. et al. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat. Immunol. 19, 291–301 (2018).
Lu, L., Barbi, J. & Pan, F. The regulation of immune tolerance by FOXP3. Nat. Rev. Immunol. 17, 703–717 (2017).
Gu, Y. Z., Hogenesch, J. B. & Bradfield, C. A. The PAS superfamily: sensors of environmental and developmental signals. Annu. Rev. Pharmacol. Toxicol. 40, 519–561 (2000).
Lamas, B., Natividad, J. M. & Sokol, H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 11, 1024–1038 (2018).
Zhou, L. AHR function in lymphocytes: emerging concepts. Trends Immunol. 37, 17–31 (2016).
Denison, M. S. & Nagy, S. R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43, 309–334 (2003).
Wang, X. et al. AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR–SP1 interaction functioning as a genetic marker for vitiligo. Sci. Rep. 5, 13542 (2015).
Kerkvliet, N. I., Shepherd, D. M. & Baecher-Steppan, L. T lymphocytes are direct, aryl hydrocarbon receptor (AhR)-dependent targets of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): AhR expression in both CD4+ and CD8+ T cells is necessary for full suppression of a cytotoxic T lymphocyte response by TCDD. Toxicol. Appl. Pharmacol. 185, 146–152 (2002).
Funatake, C. J., Marshall, N. B., Steppan, L. B., Mourich, D. V. & Kerkvliet, N. I. Cutting edge: activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin generates a population of CD4+CD25+ cells with characteristics of regulatory T cells. J. Immunol. 175, 4184–4188 (2005).
Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).
Zhang, L. et al. Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor. Invest. Ophthalmol. Vis. Sci. 51, 2109–2117 (2010).
Fernandez-Salguero, P. et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268, 722–726 (1995).
Elizondo, G., Rodriguez-Sosa, M., Estrada-Muniz, E., Gonzalez, F. J. & Vega, L. Deletion of the aryl hydrocarbon receptor enhances the inflammatory response to Leishmania major infection. Int. J. Biol. Sci. 7, 1220–1229 (2011).
Wincent, E. et al. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J. Biol. Chem. 284, 2690–2696 (2009).
Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).
Nukaya, M. & Bradfield, C. A. Conserved genomic structure of the Cyp1a1 and Cyp1a2 loci and their dioxin responsive elements cluster. Biochem. Pharmacol. 77, 654–659 (2009).
Gutierrez-Vazquez, C. & Quintana, F. J. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48, 19–33 (2018).
Xiong, L. et al. Ahr–Foxp3–RORγt axis controls gut homing of CD4+ T cells by regulating GPR15. Sci. Immunol. 5, eaaz7277 (2020). This key publication shows that interactions between AHR, FOXP3 and RORγt finely regulate the expression of GPR15 at the epigenetic level to orchestrate Treg cell gut homing.
Kim, S. V. et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 340, 1456–1459 (2013).
Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).
Maruyama, T., Konkel, J. E., Zamarron, B. F. & Chen, W. The molecular mechanisms of Foxp3 gene regulation. Semin. Immunol. 23, 418–423 (2011).
Yang, X. O. et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).
Tran, D. Q., Ramsey, H. & Shevach, E. M. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-β dependent but does not confer a regulatory phenotype. Blood 110, 2983–2990 (2007).
Okamura, T. et al. CD4+CD25–LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc. Natl Acad. Sci. USA 106, 13974–13979 (2009).
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).
Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).
Vahedi, G. et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520, 558–562 (2015).
Oyake, T. et al. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol. Cell Biol. 16, 6083–6095 (1996).
Richer, M. J., Lang, M. L. & Butler, N. S. T cell fates zipped up: how the Bach2 basic leucine zipper transcriptional repressor directs T cell differentiation and function. J. Immunol. 197, 1009–1015 (2016).
Afzali, B. et al. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat. Immunol. 18, 813–823 (2017).
Roychoudhuri, R. et al. BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis. Nature 498, 506–510 (2013). This paper shows a key role for BACH2 expression within Treg cells and its role in the prevention of autoimmunity.
Kuwahara, M. et al. Bach2–Batf interactions control TH2-type immune response by regulating the IL-4 amplification loop. Nat. Commun. 7, 12596 (2016).
Roychoudhuri, R. et al. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat. Immunol. 17, 851–860 (2016).
Imianowski, C. J. et al. BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis. J. Exp. Med. 219, e20211476 (2022).
Yao, C. et al. BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells. Nat. Immunol. 22, 370–380 (2021).
Sidwell, T. et al. Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis. Nat. Commun. 11, 252 (2020).
Rincon, M. & Flavell, R. A. AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes. EMBO J. 13, 4370–4381 (1994).
Grant, F. M. et al. BACH2 drives quiescence and maintenance of resting Treg cells to promote homeostasis and cancer immunosuppression. J. Exp. Med. 217, e20190711 (2020). Together with Sidwell et al. (2020), this paper provides evidence that BACH2 prevents premature differentiation of effector Treg cells.
Kim, E. H. et al. Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice. J. Immunol. 192, 985–995 (2014).
Do, J. S. et al. Foxp3 expression in induced T regulatory cells derived from human umbilical cord blood vs. adult peripheral blood. Bone Marrow Transpl. 53, 1568–1577 (2018).
Contreras, A. et al. BACH2 in Tregs limits the number of adipose tissue regulatory T cells and restrains type 2 immunity to fungal allergens. J. Immunol. Res. 2022, 6789055 (2022).
Povoleri, G. A. M. et al. Human retinoic acid-regulated CD161+ regulatory T cells support wound repair in intestinal mucosa. Nat. Immunol. 19, 1403–1414 (2018). This paper identifies CD161+ Treg cells as a highly suppressive subset of Treg cells that produce IL-17 and possess wound healing properties in the gut.
Pesenacker, A. M. et al. CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines. Blood 121, 2647–2658 (2013).
Rutgeerts, P., Vermeire, S. & Van Assche, G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target? Gut 56, 453–455 (2007).
Chauss, D. et al. Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells. Nat. Immunol. 23, 62–74 (2022).
McAllister, K. et al. Identification of BACH2 and RAD51B as rheumatoid arthritis susceptibility loci in a meta-analysis of genome-wide data. Arthritis Rheum. 65, 3058–3062 (2013).
Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat. Genet. 42, 1118–1125 (2010).
International Multiple Sclerosis Genetics Consortium et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).
Cooper, J. D. et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat. Genet. 40, 1399–1401 (2008).
Ferreira, M. A. et al. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378, 1006–1014 (2011).
Mouri, K. et al. Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells. Nat. Genet. 54, 603–612 (2022).
Hoshino, H. et al. Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. J. Biol. Chem. 275, 15370–15376 (2000).
Ando, R. et al. The transcription factor Bach2 is phosphorylated at multiple sites in murine B cells but a single site prevents its nuclear localization. J. Biol. Chem. 291, 1826–1840 (2016).
Yu, X. et al. SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation. Nat. Commun. 9, 3157 (2018). This work identifies SENP3 as a key molecule regulating the function and stability of Treg cells by controlling the nuclear localization of BACH2.
Hay, R. T. SUMO: a history of modification. Mol. Cell 18, 1–12 (2005).
Huang, C. et al. SENP3 is responsible for HIF-1 transactivation under mild oxidative stress via p300 de-SUMOylation. EMBO J. 28, 2748–2762 (2009).
Kim, H. R. et al. Reactive oxygen species prevent imiquimod-induced psoriatic dermatitis through enhancing regulatory T cell function. PLoS ONE 9, e91146 (2014).
Gelderman, K. A., Hultqvist, M., Holmberg, J., Olofsson, P. & Holmdahl, R. T cell surface redox levels determine T cell reactivity and arthritis susceptibility. Proc. Natl Acad. Sci. USA 103, 12831–12836 (2006).
Di Santo, J. P. Immunology. A guardian of T cell fate. Science 329, 44–45 (2010).
Albu, D. I. et al. BCL11B is required for positive selection and survival of double-positive thymocytes. J. Exp. Med. 204, 3003–3015 (2007).
Califano, D. et al. Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis. J. Clin. Invest. 124, 174–187 (2014).
Califano, D. et al. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 43, 354–368 (2015).
Cismasiu, V. B. et al. BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter. Oncogene 24, 6753–6764 (2005).
Cismasiu, V. B. et al. BCL11B participates in the activation of IL2 gene expression in CD4+ T lymphocytes. Blood 108, 2695–2702 (2006).
Vanvalkenburgh, J. et al. Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. J. Exp. Med. 208, 2069–2208 (2011).
Hasan, S. N. et al. Bcl11b prevents catastrophic autoimmunity by controlling multiple aspects of a regulatory T cell gene expression program. Sci. Adv. 5, eaaw0706 (2019).
Drashansky, T. T. et al. Bcl11b prevents fatal autoimmunity by promoting T(reg) cell program and constraining innate lineages in T(reg) cells. Sci. Adv. 5, eaaw0480 (2019). Together with Hasan et al. (2019), this paper identifies a critical role for BCL-11B in enhancing FOXP3 expression and Treg cell-associated genes.
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).
Kim, H. J. et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 350, 334–339 (2015).
Chougnet, C. & Hildeman, D. Helios — controller of Treg stability and function. Transl. Cancer Res. 5, S338–S341 (2016).
Rieder, S. A. et al. Eos is redundant for regulatory T cell function but plays an important role in IL-2 and TH17 production by CD4+ conventional T cells. J. Immunol. 195, 553–563 (2015).
Pan, F. et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 325, 1142–1146 (2009).
Raffin, C. et al. Human memory Helios–FOXP3+ regulatory T cells (Tregs) encompass induced Tregs that express Aiolos and respond to IL-1β by downregulating their suppressor functions. J. Immunol. 191, 4619–4627 (2013).
Gokhale, A. S., Gangaplara, A., Lopez-Occasio, M., Thornton, A. M. & Shevach, E. M. Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity. J. Autoimmun. 105, 102300 (2019).
Heller, J. J. et al. Restriction of IL-22-producing T cell responses and differential regulation of regulatory T cell compartments by zinc finger transcription factor Ikaros. J. Immunol. 193, 3934–3946 (2014).
Lyon de Ana, C., Arakcheeva, K., Agnihotri, P., Derosia, N. & Winandy, S. Lack of Ikaros deregulates inflammatory gene programs in T cells. J. Immunol. 202, 1112–1123 (2019). This study shows that conditional deletion of Ikaros in CD4+ T cells impairs Treg cell differentiation and promotes TH17 cell-mediated autoimmunity.
Graves, D. T. & Milovanova, T. N. Mucosal immunity and the FOXO1 transcription factors. Front. Immunol. 10, 2530 (2019).
Agnihotri, P., Robertson, N. M., Umetsu, S. E., Arakcheeva, K. & Winandy, S. Lack of Ikaros cripples expression of Foxo1 and its targets in naive T cells. Immunology 152, 494–506 (2017).
Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat. Immunol. 11, 618–627 (2010).
Yu, X. et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol. 10, 48–57 (2009).
Lucca, L. E. et al. TIGIT signaling restores suppressor function of TH1 Tregs. JCI Insight 4, e124427 (2019).
Georgopoulos, K. et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 79, 143–156 (1994).
Mullighan, C. G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008).
Yap, W. H., Yeoh, E., Tay, A., Brenner, S. & Venkatesh, B. STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells. FEBS Lett. 579, 4470–4478 (2005).
Qu, S. et al. Common variants near IKZF1 are associated with primary Sjogren’s syndrome in Han Chinese. PLoS ONE 12, e0177320 (2017).
Hoshino, A. et al. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J. Allergy Clin. Immunol. 140, 223–231 (2017).
Hoshino, A. et al. Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation. Sci. Immunol. 7, eabi7160 (2022).
Toubai, T. et al. Ikaros deficiency in host hematopoietic cells separates GVL from GVHD after experimental allogeneic hematopoietic cell transplantation. Oncoimmunology 4, e1016699 (2015).
Yasui, D., Miyano, M., Cai, S., Varga-Weisz, P. & Kohwi-Shigematsu, T. SATB1 targets chromatin remodelling to regulate genes over long distances. Nature 419, 641–645 (2002).
Cai, S., Lee, C. C. & Kohwi-Shigematsu, T. SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat. Genet. 38, 1278–1288 (2006).
Alvarez, J. D. et al. The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development. Genes Dev. 14, 521–535 (2000).
Dickinson, L. A., Joh, T., Kohwi, Y. & Kohwi-Shigematsu, T. A tissue-specific MAR/SAR DNA-binding protein with unusual binding site recognition. Cell 70, 631–645 (1992).
Kitagawa, Y. et al. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat. Immunol. 18, 173–183 (2017). This study indicates that SATB1 is a Treg cell-specific super enhancer crucial for Treg cell fate decision in thymocytes before FOXP3 expression.
Beyer, M. et al. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat. Immunol. 12, 898–907 (2011). This paper shows that SATB1-mediated modulation of global chromatin remodelling is repressed by FOXP3-dependent mechanisms in mature Treg cells.
Kondo, M. et al. SATB1 plays a critical role in establishment of immune tolerance. J. Immunol. 196, 563–572 (2016).
Yasuda, K. et al. Satb1 regulates the effector program of encephalitogenic tissue TH17 cells in chronic inflammation. Nat. Commun. 10, 549 (2019).
International Multiple Sclerosis Genetics Consortium et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet. 45, 1353–1360 (2013).
Akimova, T. et al. Human lung tumor FOXP3+ Tregs upregulate four “Treg-locking” transcription factors. JCI Insight 2, e94075 (2017).
Li, X. F. et al. Inhibition of SATB1 expression in regulatory T cells contributes to hepatitis B virus-related chronic liver inflammation. Mol. Med. Rep. 11, 231–236 (2015).
Wang, Y. et al. Overexpression of SATB1 gene inhibits the immunosuppressive function of regulatory T cells in chronic hepatitis B. Ann. Clin. Lab. Sci. 47, 403–408 (2017).
Zhao, G. N., Jiang, D. S. & Li, H. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. Biochim. Biophys. Acta 1852, 365–378 (2015).
Klein, U. et al. Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat. Immunol. 7, 773–782 (2006).
Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).
Brustle, A. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nat. Immunol. 8, 958–966 (2007).
Man, K. et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14, 1155–1165 (2013).
Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).
Honma, K. et al. Interferon regulatory factor 4 negatively regulates the production of proinflammatory cytokines by macrophages in response to LPS. Proc. Natl Acad. Sci. USA 102, 16001–16006 (2005).
Marecki, S., Atchison, M. L. & Fenton, M. J. Differential expression and distinct functions of IFN regulatory factor 4 and IFN consensus sequence binding protein in macrophages. J. Immunol. 163, 2713–2722 (1999).
Williams, J. W. et al. Transcription factor IRF4 drives dendritic cells to promote TH2 differentiation. Nat. Commun. 4, 2990 (2013).
Rengarajan, J. et al. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J. Exp. Med. 195, 1003–1012 (2002).
Haljasorg, U. et al. Irf4 expression in thymic epithelium is critical for thymic regulatory T cell homeostasis. J. Immunol. 198, 1952–1960 (2017).
Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458, 351–356 (2009). This paper shows that FOXP3 induces the expression of IRF4 in Treg cells and confers the ability to suppress TH2 cell responses.
Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).
Bravo Garcia-Morato, M. et al. New human combined immunodeficiency caused by interferon regulatory factor 4 (IRF4) deficiency inherited by uniparental isodisomy. J. Allergy Clin. Immunol. 141, 1924–1927.e18 (2018).
Alvisi, G. et al. IRF4 instructs effector Treg differentiation and immune suppression in human cancer. J. Clin. Invest. 130, 3137–3150 (2020).
Biswas, P. S., Bhagat, G. & Pernis, A. B. IRF4 and its regulators: evolving insights into the pathogenesis of inflammatory arthritis? Immunol. Rev. 233, 79–96 (2010).
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).
Keller, A. D. & Maniatis, T. Identification and characterization of a novel repressor of β-interferon gene expression. Genes Dev. 5, 868–879 (1991).
Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).
Turner, C. A. Jr., Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 (1994).
Bankoti, R. et al. Differential regulation of effector and regulatory T cell function by Blimp1. Sci. Rep. 7, 12078 (2017).
Kallies, A. et al. Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat. Immunol. 7, 466–474 (2006).
Imielinski, M. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41, 1335–1340 (2009).
Gateva, V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).
Han, J. W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).
Anderson, C. A. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 43, 246–252 (2011).
Martins, G. A. et al. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol. 7, 457–465 (2006).
Garg, G. et al. Blimp1 prevents methylation of Foxp3 and loss of regulatory T cell identity at sites of inflammation. Cell Rep. 26, 1854–1868 e1855 (2019). This study shows that BLIMP1 restrains methylation of CNS2 in the Foxp3 locus to preserve Treg cell stability in the brain.
Ogawa, C. et al. Blimp-1 functions as a molecular switch to prevent inflammatory activity in Foxp3+RORγt+ regulatory T cells. Cell Rep. 25, 19–28 e15 (2018). This paper shows that BLIMP1 binds to the IL17 locus and represses production of IL-17 in RORγt+FOXP3+ Treg cells.
Rajbhandari, P. et al. IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure. Cell 172, 218–233.e17 (2018).
Beppu, L. Y. et al. Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis. JCI Insight 6, e140644 (2021).
Lin, M. H. et al. T cell-specific BLIMP-1 deficiency exacerbates experimental autoimmune encephalomyelitis in nonobese diabetic mice by increasing TH1 and TH17 cells. Clin. Immunol. 151, 101–113 (2014).
Lin, M. H. et al. B lymphocyte-induced maturation protein 1 (BLIMP-1) attenuates autoimmune diabetes in NOD mice by suppressing TH1 and TH17 cells. Diabetologia 56, 136–146 (2013).
Hu, M. et al. Infiltrating Foxp3+ regulatory T cells from spontaneously tolerant kidney allografts demonstrate donor-specific tolerance. Am. J. Transpl. 13, 2819–2830 (2013).
Norton, S. E. et al. High-dimensional mass cytometric analysis reveals an increase in effector regulatory T cells as a distinguishing feature of colorectal tumors. J. Immunol. 202, 1871–1884 (2019).
Betz, B. C. et al. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J. Exp. Med. 207, 933–942 (2010).
Murphy, T. L., Tussiwand, R. & Murphy, K. M. Specificity through cooperation: BATF–IRF interactions control immune-regulatory networks. Nat. Rev. Immunol. 13, 499–509 (2013).
Schraml, B. U. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405–409 (2009).
Delacher, M. et al. Precursors for nonlymphoid-tissue Treg cells reside in secondary lymphoid organs and are programmed by the transcription factor BATF. Immunity 52, 295–312.e11 (2020).
Delacher, M. et al. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells. Immunity 54, 702–720.e17 (2021).
Wang, C. et al. BATF is required for normal expression of gut-homing receptors by T helper cells in response to retinoic acid. J. Exp. Med. 210, 475–489 (2013).
Xu, C. et al. BATF regulates T regulatory cell functional specification and fitness of triglyceride metabolism in restraining allergic responses. J. Immunol. 206, 2088–2100 (2021).
Hayatsu, N. et al. Analyses of a mutant Foxp3 allele reveal BATF as a critical transcription factor in the differentiation and accumulation of tissue regulatory T cells. Immunity 47, 268–283.e9 (2017).
Itahashi, K. et al. BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors. Sci. Immunol. 7, eabk0957 (2022). Together with Xu et al. (2021), this work shows that BATF regulates a key gene signature in Treg cells and specific ablation of Batf results in an inflammatory disorder characterized by TH2-type dominant responses.
Cowell, I. G. E4BP4/NFIL3, a PAR-related bZIP factor with many roles. Bioessays 24, 1023–1029 (2002).
Cowell, I. G. & Hurst, H. C. Transcriptional repression by the human bZIP factor E4BP4: definition of a minimal repression domain. Nucleic Acids Res. 22, 59–65 (1994).
Zhang, W. et al. Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter. Mol. Cell Biol. 15, 6055–6063 (1995).
Kashiwada, M. et al. IL-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching. Proc. Natl Acad. Sci. USA 107, 821–826 (2010).
Gascoyne, D. M. et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nat. Immunol. 10, 1118–1124 (2009).
Kamizono, S. et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 206, 2977–2986 (2009).
Kashiwada, M., Pham, N. L., Pewe, L. L., Harty, J. T. & Rothman, P. B. NFIL3/E4BP4 is a key transcription factor for CD8α+ dendritic cell development. Blood 117, 6193–6197 (2011).
Kobayashi, T. et al. NFIL3-deficient mice develop microbiota-dependent, IL-12/23-driven spontaneous colitis. J. Immunol. 192, 1918–1927 (2014).
Kashiwada, M., Cassel, S. L., Colgan, J. D. & Rothman, P. B. NFIL3/E4BP4 controls type 2 T helper cell cytokine expression. EMBO J. 30, 2071–2082 (2011).
Layland, L. E. et al. Pronounced phenotype in activated regulatory T cells during a chronic helminth infection. J. Immunol. 184, 713–724 (2010).
Kim, H. S., Sohn, H., Jang, S. W. & Lee, G. R. The transcription factor NFIL3 controls regulatory T-cell function and stability. Exp. Mol. Med. 51, 80 (2019). This study shows that NFIL3 directly binds to and negatively regulates the expression of FOXP3, in a mechanism that induces methylation at the FOXP3 locus CpG sites.
Motomura, Y. et al. The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat. Immunol. 12, 450–459 (2011).
Bagadia, P., Huang, X., Liu, T. T. & Murphy, K. M. Shared transcriptional control of innate lymphoid cell and dendritic cell development. Annu. Rev. Cell Dev. Biol. 35, 381–406 (2019).
Frias, A. B. Jr. et al. The transcriptional regulator Id2 is critical for adipose-resident regulatory T cell differentiation, survival, and function. J. Immunol. 203, 658–664 (2019).
Miyazaki, M. et al. Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat. Immunol. 15, 767–776 (2014).
Masson, F. et al. Id2 represses E2A-mediated activation of IL-10 expression in T cells. Blood 123, 3420–3428 (2014).
Hwang, S. M. et al. Inflammation-induced Id2 promotes plasticity in regulatory T cells. Nat. Commun. 9, 4736 (2018).
Boland, B. S. et al. Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses. Sci. Immunol. 5, eabb4432 (2020).
Schlenner, S. et al. NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology. Ann. Rheum. Dis. 78, 342–349 (2019).
Sakaguchi, S., Vignali, D. A., Rudensky, A. Y., Niec, R. E. & Waldmann, H. The plasticity and stability of regulatory T cells. Nat. Rev. Immunol. 13, 461–467 (2013).
Polansky, J. K. et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654–1663 (2008).
Deknuydt, F., Bioley, G., Valmori, D. & Ayyoub, M. IL-1β and IL-2 convert human Treg into TH17 cells. Clin. Immunol. 131, 298–307 (2009).
Beriou, G. et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113, 4240–4249 (2009). This paper demonstrates that IL-17-producing FOXP3+ Treg cells induced by pro-inflammatory cytokines maintain suppressive function and express CCR6.
Hoffmann, P. et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur. J. Immunol. 39, 1088–1097 (2009).
Xu, L., Kitani, A., Fuss, I. & Strober, W. Cutting edge: regulatory T cells induce CD4+CD25–Foxp3– T cells or are self-induced to become TH17 cells in the absence of exogenous TGF-β. J. Immunol. 178, 6725–6729 (2007).
Komatsu, N. et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl Acad. Sci. USA 106, 1903–1908 (2009).
Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009). This publication indicates that Treg cells lose expression of FOXP3 in inflamed microenvironments and acquire an effector-memory phenotype.
Noval Rivas, M. et al. Regulatory T cell reprogramming toward a TH2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42, 512–523 (2015).
Rubtsov, Y. P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).
Hori, S. Regulatory T cell plasticity: beyond the controversies. Trends Immunol. 32, 295–300 (2011).
Hori, S. Developmental plasticity of Foxp3+ regulatory T cells. Curr. Opin. Immunol. 22, 575–582 (2010).
Hori, S. Lineage stability and phenotypic plasticity of Foxp3+ regulatory T cells. Immunol. Rev. 259, 159–172 (2014).
Szabo, S. J. et al. A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100, 655–669 (2000).
Hwang, E. S., Szabo, S. J., Schwartzberg, P. L. & Glimcher, L. H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307, 430–433 (2005).
Lazarevic, V. et al. T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat. Immunol. 12, 96–104 (2011).
Djuretic, I. M. et al. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat. Immunol. 8, 145–153 (2007).
Amarnath, S. et al. Tbet is a critical modulator of FoxP3 expression in autoimmune graft-versus-host disease. Haematologica 102, 1446–1456 (2017).
Levine, A. G. et al. Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546, 421–425 (2017). This report shows that T-bet expression is essential for maintaining Treg cell suppressive function for controlling TH1 cell and CD8+ T cell responses.
Dominguez-Villar, M., Baecher-Allan, C. M. & Hafler, D. A. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat. Med. 17, 673–675 (2011). This paper identifies IFNγ+T-bet+ Treg cells in patients with multiple sclerosis and suggests that they may have reduced in vitro suppressive function.
Wang, Z. et al. Role of IFN-γ in induction of Foxp3 and conversion of CD4+CD25– T cells to CD4+ Tregs. J. Clin. Invest. 116, 2434–2441 (2006).
Di Giovangiulio, M. et al. Tbet expression in regulatory T cells is required to initiate TH1-mediated colitis. Front. Immunol. 10, 2158 (2019).
Afkarian, M. et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat. Immunol. 3, 549–557 (2002).
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). This report shows that T-bet expression is essential for Treg cells to access sites of TH1-type inflammation.
Tan, T. G., Mathis, D. & Benoist, C. Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proc. Natl Acad. Sci. USA 113, 14103–14108 (2016).
Warunek, J. et al. Tbet expression by regulatory T cells is needed to protect against TH1-mediated immunopathology during toxoplasma infection in mice. Immunohorizons 5, 931–943 (2021).
Kachler, K., Holzinger, C., Trufa, D. I., Sirbu, H. & Finotto, S. The role of Foxp3 and Tbet co-expressing Treg cells in lung carcinoma. Oncoimmunology 7, e1456612 (2018).
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).
Zheng, W. & Flavell, R. A. The transcription factor GATA-3 is necessary and sufficient for TH2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).
Ho, I. C. et al. Human GATA-3: a lineage-restricted transcription factor that regulates the expression of the T cell receptor α gene. EMBO J. 10, 1187–1192 (1991).
Chapoval, S., Dasgupta, P., Dorsey, N. J. & Keegan, A. D. Regulation of the T helper cell type 2 (TH2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J. Leukoc. Biol. 87, 1011–1018 (2010).
Wohlfert, E. A. et al. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J. Clin. Invest. 121, 4503–4515 (2011).
Wang, Y., Su, M. A. & Wan, Y. Y. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35, 337–348 (2011).
Siede, J. et al. IL-33 receptor-expressing regulatory T cells are highly activated, TH2 biased and suppress CD4 T cell proliferation through IL-10 and TGFβ release. PLoS ONE 11, e0161507 (2016).
Hayakawa, M. et al. T-helper type 2 cell-specific expression of the ST2 gene is regulated by transcription factor GATA-3. Biochim. Biophys. Acta 1728, 53–64 (2005).
Sawant, D. V. et al. Bcl6 controls the TH2 inflammatory activity of regulatory T cells by repressing Gata3 function. J. Immunol. 189, 4759–4769 (2012).
Sakai, R. et al. Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury. Cell Mol. Immunol. 18, 1249–1261 (2021).
Kalekar, L. A. et al. Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses. Sci. Immunol. 4, eaaw2910 (2019). This paper shows that skin Treg cells express high levels of GATA3 and have a key role during dermal fibrosis.
Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).
Kurebayashi, S. et al. Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl Acad. Sci. USA 97, 10132–10137 (2000).
Eberl, G. et al. An essential function for the nuclear receptor RORγ(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5, 64–73 (2004).
Croft, C. A. et al. Notch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation. Nat. Commun. 13, 4344 (2022).
Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Lochner, M. et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+Foxp3+RORγt+ T cells. J. Exp. Med. 205, 1381–1393 (2008).
Sefik, E. et al. MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 349, 993–997 (2015).
Bhaumik, S., Mickael, M. E., Moran, M., Spell, M. & Basu, R. RORγt promotes Foxp3 expression by antagonizing the effector program in colonic regulatory T cells. J. Immunol. 207, 2027–2038 (2021).
Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).
Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).
Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).
Ohnmacht, C. et al. MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349, 989–993 (2015).
Yang, B. H. et al. Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 9, 444–457 (2016).
Zhou, L. et al. IL-6 programs TH17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).
Kedmi, R. et al. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation. Nature 610, 737–743 (2022). Together with Sefik et al. (2015), this article shows that RORγt is preferentially expressed in colonic Treg cells and induced by the gut microbiota.
Akagbosu, B. et al. Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota. Nature 610, 752–760 (2022).
Lyu, M. et al. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature 610, 744–751 (2022).
Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).
Afzali, B. et al. CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. Eur. J. Immunol. 43, 2043–2054 (2013).
Ichiyama, K. et al. Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. J. Biol. Chem. 283, 17003–17008 (2008).
Neumann, C. et al. c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis. Nat. Immunol. 20, 471–481 (2019).
Imbratta, C., Hussein, H., Andris, F. & Verdeil, G. c-MAF, a Swiss army knife for tolerance in lymphocytes. Front. Immunol. 11, 206 (2020).
Gabrysova, L. et al. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells. Nat. Immunol. 19, 497–507 (2018).
Xu, J. et al. c-Maf regulates IL-10 expression during TH17 polarization. J. Immunol. 182, 6226–6236 (2009).
Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373–377 (2018).
Kullberg, M. C. et al. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and γ interferon-dependent mechanism. Infect. Immun. 66, 5157–5166 (1998).
Fukuda, T. et al. Disruption of the Bcl6 gene results in an impaired germinal center formation. J. Exp. Med. 186, 439–448 (1997).
Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and TH2-type inflammation. Nat. Genet. 16, 161–170 (1997).
Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).
Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).
Koenig, A. et al. NFATc1/αA and Blimp-1 support the follicular and effector phenotype of Tregs. Front. Immunol. 12, 791100 (2021). This paper shows that BLIMP1 cooperates with NFATc1 to mediate CXCR5 transactivation for promoting the migration of TFR cells into B cell follicles.
Linterman, M. A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).
Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).
Aloulou, M. et al. Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells. Nat. Commun. 7, 10579 (2016).
Kumar, S. et al. Developmental bifurcation of human T follicular regulatory cells. Sci. Immunol. 6, eabd8411 (2021).
Fu, W. et al. Deficiency in T follicular regulatory cells promotes autoimmunity. J. Exp. Med. 215, 815–825 (2018).
Wen, Y. et al. Imbalance of circulating CD4+CXCR5+FOXP3+ TFR-like cells and CD4+CXCR5+FOXP3– TFH-like cells in myasthenia gravis. Neurosci. Lett. 630, 176–182 (2016).
Fonseca, V. R. et al. Human blood TFR cells are indicators of ongoing humoral activity not fully licensed with suppressive function. Sci. Immunol. 2, eaan1487 (2017).
Acknowledgements
This work was supported by extramural research programmes of the US National Institutes of Health (NIH) (R35GM138283 to M.K.) and (in part) by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases (project number ZIA/DK075149 to B.A.). We also acknowledge support from the Purdue University Center for Cancer Research (P30CA023168). We thank V. Lazaveric (NIH) for constructive feedback on the first draft of the manuscript.
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Trujillo-Ochoa, J.L., Kazemian, M. & Afzali, B. The role of transcription factors in shaping regulatory T cell identity. Nat Rev Immunol 23, 842–856 (2023). https://doi.org/10.1038/s41577-023-00893-7
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DOI: https://doi.org/10.1038/s41577-023-00893-7
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