Relationship between CD4 Regulatory T Cells and Anergy In Vivo Lokesh A. Kalekar and Daniel L. Mueller This information is current as J Immunol 2017; 198:2527-2533; ; of October 1, 2021. doi: 10.4049/jimmunol.1602031 http://www.jimmunol.org/content/198/7/2527 References This article cites 83 articles, 33 of which you can access for free at: Downloaded from http://www.jimmunol.org/content/198/7/2527.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 1, 2021 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. Th eJournal of Brief Reviews Immunology Relationship between CD4 Regulatory T Cells and Anergy In Vivo Lokesh A. Kalekar1 and Daniel L. Mueller + Selective suppression of effector CD4 T cell functions Treg cells control tolerance to some tissue-restricted self-Ags is necessary to prevent immune cell–mediated damage Two recent studies took advantage of experimental Ags to healthy tissues. This appears especially true during (peptides derived from either the P1 bacteriophage Cre pregnancy or in individuals predisposed to autoimmu- recombinase [Cre] or the Aequorea victoria enhanced GFP + nity. Foxp3 regulatory T (Treg) cells and induction of [eGFP]) whose expression in mice was directed by transgenic anergy, an acquired state of T cell functional unrespon- 2 tissue-specific promoters, and additionally made use of pep- siveness in Foxp3 cells, have both been implicated as tide MHC class II (pMHCII) tetramers to detect polyclonal + mechanisms to suppress dangerous immune responses CD4 T cells that respond to these model self-Ags (4, 5). Downloaded from to tissue-restricted self-Ags. Anergic CD4+ T cells and Both experiments demonstrated that ubiquitous (both thy- Treg cells share a number of phenotypic and mechanis- mic and peripheral) expression of self-Ag leads to deletion of tic traits—including the expression of CD73 and folate 60–95% of the highest affinity self-specific CD4+ T cells, receptor 4, and the epigenetic modification of Treg cell with the remaining low-affinity cells left functionally unre- signature genes—and an interesting relationship be- sponsive to Ag (Fig. 1). In contrast, restriction of self-Ag tween these two subsets has recently emerged. In this expression exclusively to nonthymic tissues leads to a toler- http://www.jimmunol.org/ review, we will compare and contrast these two subsets, ance that appears to rely solely on ignorance by naive auto- as well as explore the role of anergy in the generation of reactive T cells. The strongest evidence for an active peripheral self-tolerance mechanism in these studies came in peripheral Treg cells. The Journal of Immunology, 2017, 198: 2527–2533. the form of self-Ags that were only weakly expressed in the thymus and, in particular, were otherwise restricted to mu- cosal tissues (e.g., Cre protein expression in the intestinal he self-tolerance mechanisms of T cells can be broadly brush border driven by a Vil1-Cre transgene, or expression in characterized as central or peripheral (Fig. 1). Cen- airway Clara cells driven by a Scgb1a1-Cre transgene). These tral tolerance mechanisms destroy high-affinity self- Ags induce little central deletion, and instead self-tolerance by guest on October 1, 2021 T + reactive T cells during thymic development, or else induce relies on the generation of self pMHCII-binding Foxp3 Treg their differentiation into a regulatory T (Treg)celllineage(1). cells (5). Importantly, these Treg cells appear to suppress the Nonetheless, central tolerance appears to be insufficient to conventional CD4+ T cell responses to self-Ag, because sys- + clear all self-reactive T cells, and other peripheral tolerance temic ablation of Foxp3 Treg cells at the time of a self-Ag mechanisms are necessary (2, 3). Peripheral tolerance may immunization led to a restoration of the conventional T cell rely on: 1) ignorance, wherein autoreactive T cells never clonal expansion and cytokine production response to near- encounter their cognate Ag; 2) deletion, whereby self-specific control levels (5). peripheral T cells are destroyed after TCR engagement; 3) In addition to Treg cells, several other suppressor cells have anergy, which is a state of functional unresponsiveness in- been described, such as the Tr1 cells, myeloid-derived sup- + duced upon self-Ag recognition; and/or 4) Foxp3 Treg cell– pressor cells, as well as the regulatory B cells. However, it is + mediated suppression of dangerous T cell responses against well established that Foxp3 Treg cells maintain immune ho- self-Ag. Each of these potential tolerance mechanisms has meostasis and prevent adverse immune responses throughout been clearly defined in numerous in vivo experimental sys- the life span of an individual. Foxp3 is an essential lineage- tems using TCR-transgenic responder T cells, typically at defining transcription factor of Treg cells (6, 7), because abnormally high cell frequencies. However, much less is mutations or deletion of the Foxp3 gene lead to impaired + known about self-tolerance in the natural polyclonal CD4 generation of Treg cells and cause severe autoimmunity in T cell repertoire. humans and mice (6, 8). Furthermore, instability of Foxp3 Department of Medicine, University of Minnesota Medical School, Minneapolis, MN Address correspondence and reprint requests to Dr. Daniel L. Mueller, University of 55455; and Center for Immunology, University of Minnesota Medical School, Minne- Minnesota Medical School, 2101 6th Street SE, 3-186 WMBB, Campus Delivery Code: apolis, MN 55455 2641, Minneapolis, MN 55455. E-mail address: [email protected] 1Current address: Department of Dermatology, University of California, San Francisco, Abbreviations used in this article: CNS, conserved noncoding DNA sequence; Cre, Cre San Francisco, CA. recombinase; DC, dendritic cell; eGFP, enhanced GFP; FR4, folate receptor 4; InsB, insulin B chain; Nrp1, neuropilin 1; pMHCII, peptide MHC class II; pT , peripheral Received for publication December 2, 2016. Accepted for publication January 9, 2017. reg Treg;Treg, regulatory T; Treg-me, Treg cell methylome; tTreg, thymic Treg. This work was supported by a Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign grant from the Rheumatology Research Foundation and by National Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 Institutes of Health Grant P01 AI35296. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1602031 2528 BRIEF REVIEWS: ANERGIC T CELLS AS Treg PROGENITORS Downloaded from http://www.jimmunol.org/ by guest on October 1, 2021 FIGURE 1. The role of anergy in pTreg cell generation: a model. CD4 single-positive thymocytes specific for tissue-restricted self-Ags can experience one of several fates. Abundant thymic self pMHCII presentation leads to central deletion. If self pMHCII abundance is very low, thymocytes escape to the periphery and often ignore the Ag. For the case of intermediate self pMHCII complex abundance, some thymocytes will die, some will differentiate to a Treg cell fate, and some will escape the thymus. Self-Ag–specific CD4+ T cells that escape into the periphery can recognize peripheral self pMHCII, and through the suppressive actions of Treg cells become anergic cells that express CD73 and FR4. Persistent Ag encounter induces Nrp1 expression and partial demethylation of the Treg-me in some of + the anergic T cells. Nrp1 anergic T cells then become precursors for Treg cell differentiation. Upon conversion to a stable pTreg cell lineage, anergy-derived Treg cells join the tTreg cell pool to suppress immunopathology and reinforce anergy induction. + expression allows for the transdifferentiation of Treg cells to Most Foxp3 Treg cells undergo their terminal differentia- T effector cell lineages capable of causing autoimmunity (9, tion in the thymus and are referred to as thymic Treg (tTreg) 10). Although Foxp3 is considered to be the master regulator cells, whereas others originate in the periphery (particularly at of Treg suppressive function, the expression of Foxp3 is not mucosal barrier surfaces exposed to food Ags and commensal 2 + sufficient to maintain a stable Treg cell lineage (11, 12). organisms) from conventional Foxp3 CD4 T cells and are Numerous Treg cell–specific genes are in fact expressed in- consequently called peripheral Treg (pTreg) cells (15, 16). It is dependently of Foxp3 protein, including Il2ra (the gene for believed that the self pMHCII specificity and suppressive CD25), Ctla4, Ikzf4 (Eos), and neuropilin 1 (Nrp1) (11, 13, functions of these two Treg subsets complement one another 14). These data suggest that additional lineage-defining in preventing immunopathology (17). tTreg cells are primarily factors act with Foxp3 to ensure the generation of a stable, responsible for maintaining general T cell immune homeo- functional Treg cell compartment. stasis, whereas pTreg cells control immunopathology that is The Journal of Immunology 2529 directed against tissue-restricted Ags in mucosal tissues such as plays some role in the establishment of self-tolerance in concert + the lung and gut (17). with Ag-specific Foxp3 Treg cells? Natural Treg (nTreg) cells are defined as all Treg cells gen- Historically, anergy has been defined as a state of functional + erated in vivo, and thus include tTreg cells and some pTreg inactivation wherein CD4 T cells lose the capacity to pro- cells (16).