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Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability

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Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability This information is current as Zhongmei Zhang, Wei Zhang, Jie Guo, Qianchong Gu, of October 5, 2021. Xueping Zhu and Xuyu Zhou J Immunol 2017; 198:2612-2625; Prepublished online 22 February 2017; doi: 10.4049/jimmunol.1601409 http://www.jimmunol.org/content/198/7/2612 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/02/21/jimmunol.160140 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 53 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/198/7/2612.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 5, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Activation and Functional Specialization of Regulatory T Cells Lead to the Generation of Foxp3 Instability Zhongmei Zhang,*,† Wei Zhang,* Jie Guo,* Qianchong Gu,*,† Xueping Zhu,*,† and Xuyu Zhou*,† Accumulating evidence suggests that Foxp3+ cells can downregulate the expression of Foxp3, but whether thymically derived regulatory T cells (tTregs; especially committed tTregs) are capable of downregulating Foxp3 expression and being reprog- rammed into other T effector cells remains controversial. Using a novel tTreg lineage-tracing mouse line, we were able to label epigenetically stable Foxp3+ cells derived from the thymus and demonstrate that mature tTregs are stable under homeostatic conditions. However, TCR engagement and sequential functional specialization of tTregs led to the generation of Foxp3 instability and reprogramming into the Th lineage. We further demonstrated that the signal switch from IL-2 to ICOS during Treg activation induced Treg instability and reprogramming. By using a dual lineage tracing model, we demonstrated that effector Downloaded from Tregs can revert to central Tregs, and this reversion is associated with increasing Foxp3 stability in vivo. The Journal of Immunology, 2017, 198: 2612–2625. egulatory T cells (Tregs) are a specialized sublineage of the development of tTregs, serving as the alternative insurance to CD4+ T cells that have a crucial role in the control the organism to prevent self-autoreactivity (3). In contrast, in the of immunological self-tolerance and the maintenance of periphery, GALTs exposed to a multitude of commensal bacterial R http://www.jimmunol.org/ immune homeostasis (1). Foxp3 is the lineage-specifying tran- and food Ags favor the development of pTregs to maintain im- scription factor of Tregs, whose deficiency (such as in scurfy mice mune tolerance at mucosal interfaces (4). To date, there is no and immune dysregulation, polyendocrinopathy, enteropathy, definitive marker to distinguish between these two Treg subsets. X-linked patients) results in a fatal autoimmune syndrome (2). In Thornton et al. (5) demonstrated that Helios is an Ikaros tran- contrast, ablation of Foxp3 from mature Tregs leads to loss of Treg scription factor family member exclusively expressed on tTregs, identity and switching to other types of Th cells. Thus, continued and Ag-specific Foxp3+ T cells induced in vivo by Ag feeding are expression of Foxp3 is indispensable for Treg lineage maintenance devoid of Helios expression. However, others have challenged this and immunosuppressive function (2). conclusion by using different Ag-specific pTreg-inducing systems Foxp3 can be induced either in Treg precursors in the thymus or (6). Recently, neuropilin 1 (Nrp1) was proposed as a tTreg marker, by guest on October 5, 2021 + in naive CD4 T cells in the periphery by a combination of TCR, but conventional T cells (Tconvs) can transiently upregulate Nrp1 costimulation, and cytokine signals, generating thymically derived upon Ag stimulation (7, 8). Furthermore, slight Nrp1 expression is Tregs (tTregs) and peripherally derived Tregs (pTregs), respec- also detected in newly generated induced Tregs (iTregs) in vitro tively (3). In the thymus, self-agonist ligands preferentially cause and in vivo (7, 8). Recent studies from Rudensky and colleagues (9) demonstrated that the conserved noncoding sequence (CNS)1 *Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Micro- of the Foxp3 gene, which serves as a major TGF-b sensor, is † biology, Chinese Academy of Sciences, Beijing 100101, China; and University of critical for the generation of induced pTregs but dispensable for Chinese Academy of Sciences, Beijing 100049, China tTreg development. Thus, CNS1 dependence could be a more ORCID: 0000-0002-6626-0898 (X. Zhou). reliable criterion for distinguishing tTregs and pTregs, especially Received for publication August 15, 2016. Accepted for publication January 27, 2017. under inflammatory conditions. This work was supported by National Natural Science Foundation of China Grants Although Tregs have shown great therapeutic potential for 31270959 and 31300750 and by National Key Basic Research and Development (973 curing various autoimmune diseases and preventing unwanted Program of China) Grant 2012CB917102. immune responses such as graft-versus-host disease in preclinical The raw RNA sequencing data presented in this article were submitted to the Gene animal models, precautions must be taken to ensure the identity and Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo) under accession number GSE93856. stability of Tregs for translation to the clinic. Our previous fate- Address correspondence and reprint requests to Prof. Xuyu Zhou, Key Laboratory of mapping studies demonstrated that a fraction of Tregs are not Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Acad- stable under autoimmune inflammatory conditions. These previ- emy of Sciences, 1st West Beichen, Chaoyang, Beijing 100101, China. E-mail address: ously Foxp3-expressing (exFoxp3) T cells have an activated [email protected] memory T cell phenotype, produce inflammatory cytokines, and The online version of this article contains supplemental material. confer autoimmunity upon adoptive transfer, likely participating in Abbreviations used in this article: BAC, bacterial artificial chromosome; CNS, con- served noncoding sequence; DP, double-positive; exFoxp3, previously Foxp3- a feed-forward loop in promoting the pathogenesis of autoim- expressing; GC, germinal center; iTreg, induced Treg; KI, knock-in; KO, knockout; munity (10, 11). Stable expression of Foxp3 is largely controlled LN, lymph node; MFI, mean fluorescence intensity; Nrp1, neuropilin 1; PD1, pro- by the methylation status of the CNS2 (also known as the Treg- grammed cell death 1; pTreg, peripherally derived Treg; RA, retinoic acid; Rluc, Renilla luciferase; RNA-seq, RNA sequencing; Tconv, conventional T cell; TFH, specific demethylated region) region of the Foxp3 locus (12, 13). follicular helper T; TFR, T follicular regulatory; Tg, transgenic; Treg, regulatory Demethylation of CNS2 in Tregs is mediated by Tet-dependent T cell; tTreg, thymically derived Treg; YFP, yellow fluorescent protein. oxidization and favors the recruitment of multiple transcription Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 factors such as Cbfb, Runx1, STAT5, and Foxp3 itself to the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601409 The Journal of Immunology 2613 CNS2 to further ensure stable Foxp3 expression (14, 15). Re- phenotype to a central Treg phenotype, which was also associ- cently, studies have demonstrated that genetically deleting the ated with stable expression of Foxp3. Together, the signal CNS2 enhancer of Foxp3 results in a destabilized Treg lineage, driving Treg activation and functional specialization also and CNS2-deficient mice develop spontaneous autoimmunity and prompted the generation of Foxp3 instability, which indicates that chronic inflammation (16, 17). an optimal window of signal strength could be crucial for Treg Two different models have been proposed to explain the gen- activation in vivo. eration of exFoxp3 cells. The reprogramming model suggests that Tregs can become unstable due to the remethylation of the CNS2 region of the Foxp3 locus under inflammatory conditions (11). Materials and Methods Thus, Tregs lose their Foxp3 expression and are reprogrammed Mice into Th cells. In contrast, the second model suggests that Tregs are For Foxp3 DCNS1-Cre reporter mice, the hCre-2A-eqFP650-2A-Thy1.1 a stable lineage, but a minor population of uncommitted Foxp3+ cDNA fragment was inserted immediately downstream of the Foxp3 T cells (which either come from transient Foxp3 expression during ATG translational start site by homologous recombination into a 188-kb mouse BAC (from the C57BL/6 genome; clone RP23-143D8) carrying the activation of conventional peripheral T cells or from immature
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