Th eJournal of Brief Reviews Immunology Control of Regulatory T Cell Migration, Function, and Homeostasis Daniel J. Campbell Foxp3+ regulatory T cells (Tregs) are essential for pre- are phenotypically and functionally diverse, and their localiza- venting autoimmunity and uncontrolled inflammation, tion and maintenance in different tissue sites are essential for and they modulate immune responses during infection their ability to interact with and modulate their cellular targets. and the development of cancer. Accomplishing these This Brief Review covers recent advances in understanding tasks requires the widespread distribution of Tregs in the control of Treg localization, homeostasis, and function in both lymphoid and nonlymphoid tissues, and the se- lymphoid and nonlymphoid tissue sites, with particular em- lective recruitment of Tregs to different tissue sites has phasis on how manipulation of these pathways could be ther- emerged as a key checkpoint that controls tissue inflam- apeutically beneficial in the contexts of autoimmune disease, mation in autoimmunity, infection, and cancer develop- cancer, and transplantation. ment, as well as in the context of allograft acceptance Phenotypic and functional diversity of Tregs or rejection. Additionally, Tregs are functionally di- verse, and it has become clear that some of this diversity Two pathways exist for Treg development. Differentiation of segregates with Treg localization to particular tissue sites. thymic-derived Tregs (tTregs) depends on high-affinity inter- In this article, I review the progress in understanding the actions with self-peptide/MHC class II complexes during T cell mechanisms of Treg trafficking and discuss factors development in the thymus (2, 3), whereas peripheral-derived controlling their homeostatic maintenance and func- Tregs (pTregs) develop in the periphery from naive T cell pre- tion in distinct tissue sites. The Journal of Immunology, cursors that upregulate Foxp3 when activated by foreign Ags in 2015, 195: 2507–2513. tolerogenic conditions. Specifically, activation of naive T cells inthepresenceofTGF-b and the absence of inflammatory cytokines, such as IFN-g,IL-4,orIL-6,resultsinpTregde- he discovery of dominant tolerance mediated by dif- velopment (4); as such, pTregs are particularly important ferent populations of regulatory T cells (Tregs) ∼20 y for tolerance at mucosal surfaces against commensal micro- ago initiated a flurry of research into the cellular and organisms and harmless environmental Ags. However, de- by guest on September 30, 2021. Copyright 2015 Pageant Media Ltd. T molecular basis for the function of these cells. A key discovery finitive markers differentiating tTregs and pTregs have not occurred when several groups found that the transcription fac- been identified; thus, in most cases, the relative contributions tor Foxp3 is essential for the proper development and function of tTregs and pTregs to the Treg pool in different tissues and of Tregs (1). Indeed, loss of Treg function due to mutations in inflammatory settings have not been determined. Foxp3 results in fatal systemic autoimmunity in both mice and Initial analysis of homing receptor expression by Tregs in- humans, and defects in the development, function, or mainte- dicated that, rather than having a uniform phenotype, Tregs nance of Tregs were implicated in the pathogenesis of a host of could be subdivided into distinct populations that expressed autoimmune and inflammatory diseases. Conversely, Tregs can adhesion and chemoattractant receptors that would target them https://www.jimmunol.org inhibit pathogen clearance and promote chronic infection, and to a range of tissues and inflammatory sites (5). These included they represent a significant barrier to effective tumor immu- cells that would be targeted to secondary lymphoid organs, to notherapy. Therefore, understanding the control of Treg ho- specific nonlymphoid tissues, such as the skin and intestines, meostasis and function has significant therapeutic implications. and to sites of Th1-, Th2-, or Th17-mediated inflammatory Based on the discovery of Foxp3 as a master transcription responses. Accordingly, Tregs are broadly distributed in lym- factor, a number of experimental tools were developed that al- phoid and nonlymphoid tissue sites, even in the absence of any Downloaded from lowed for the precise identification and molecular characteriza- overt inflammation (6), and many studies demonstrated that tion of Foxp3-expressing cells, resulting in unparalleled insights Tregs function in both lymphoid and nonlymphoid tissues into the biology of Tregs. A central theme that emerged from to prevent the initiation of aberrant immune responses or to these studies is that, like conventional CD4+ Th cells, Tregs dampen ongoing inflammatory responses, respectively. Immunology Program, Benaroya Research Institute, Seattle, WA 98101; and Depart- Address correspondence and reprint requests to Dr. Daniel J. Campbell, Benaroya ment of Immunology, University of Washington School of Medicine, Seattle, WA Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA 98101-2795. E-mail 98195 address: [email protected] Received for publication April 20, 2015. Accepted for publication July 2, 2015. Abbreviations used in this article: cTreg, central Treg; DC, dendritic cell; eTreg, effector Treg; FRC, fibroblastic reticular cell; mTreg, memory Treg; pTreg, peripheral-derived This work was supported in part by Grants AR055695, DK072295, HL098067, and Treg; RA, retinoic acid; Treg, regulatory T cell; tTreg, thymic-derived Treg. AI067750 from the National Institutes of Health. Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500801 2508 BRIEF REVIEWS: CONTROL OF Tregs Tregs are known to occupy their own homeostatic niche, as the immunosuppressive enzyme IDO (19). Consistent with this evidenced by the ability of small numbers of Tregs to expand model, loss of CLTA-4 expression in Tregs resulted in lympho- dramatically when transferred into Treg-deficient hosts (7). proliferative disease marked by aberrant T cell activation, as well However, the presence of significant populations of Tregs in as severe lymphadenopathy and splenomegaly (20). Interest- multiple lymphoid and nonlymphoid organs raises the question ingly, CTLA-4 also mediates direct interactions between Tregs of whether Tregs in different tissues are maintained by distinct and effector T cells in lymph nodes, and although the functional homeostatic mechanisms. Indeed, despite the incredibly com- importance of these interactions is not clear, they may also con- plex patterns of homing receptor expression by Tregs, based on tribute to inhibition of T cell priming (15). differential expression of the activation marker CD44 and the In contrast to naive T cells, Tregs in secondary lymphoid lymph node homing receptor CD62L, Tregs can be broadly organs express low levels of the IL-7R component CD127 (21); divided into CD44loCD62L+ central Tregs (cTregs) andCD44hi therefore, unlike naive T cells, they do not rely on IL-7 for their CD62Llo/- effector Tregs (eTregs) that display distinct ho- homeostatic maintenance. Instead, Tregs are characterized by meostatic behaviors (8). Although cTregs are quiescent, express constitutive expression of the high-affinity IL-2R component high-levels of antiapoptotic molecules (e.g., Bcl-2 and Mcl-1), CD25. Indeed, IL-2 serves many similar functions for Tregs and recirculate through the secondary lymphoid tissues, eTregs that IL-7 does for naive T cells. For example, like naive T cells are highly proliferative, are prone to apoptosis due to decreased that respond to paracrine IL-7 produced by fibroblastic reticular expression of Bcl-2 and Mcl-1, and are the dominant Treg cells (FRCs), Tregs cannot produce their own IL-2; instead, they population in nonlymphoid tissues. Unlike recirculating rely on paracrine IL-2 produced by activated T cells (22, 23). cTregs, parabiosis experiments indicated that eTregs in non- Additionally, just as IL-7 helps to maintain naive T cells without lymphoid tissues are largely tissue-resident. Thus, there appears driving robust homeostatic proliferation, IL-2 signaling in Tregs to be a division of labor between cTregs and eTregs that are in secondary lymphoid tissues is limited to quiescent cTregs and specialized for functioning either within the secondary lym- is not associated with the high level of homeostatic prolifera- phoidtissues to inhibitT cellpriming or in specific nonlymphoid tion observed in eTregs (8). Indeed, cTregs are particularly depen- tissues and inflammatory sites to dampen effector cell responses, dent on IL-2 for their homeostatic maintenance, whereas eTreg respectively (9, 10). However, the function of both cTregs and maintenance andproliferation are largely IL-2 independent. The eTregs likely depends on their precise positioning that facilitates ability of cTregs to selectively access IL-2 in vivo is due to their the cellular interactions that promote Treg function and CCR7-dependent migration into organized T cells zones in homeostasis. secondary lymphoid tissues (8). Interestingly, FRCs are the primary sources of the CCR7 ligands CCL19 and CCL21 in Treg function and maintenance in secondary lymphoid organs the secondary lymphoid organs (24). Therefore, it appears that Before exiting the thymus, tTregs upregulate the expression of whereas FRCs control naive T cell homeostasis via direct pro- the homing receptors CD62L