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Regulatory T cells Ethan Shevach and Todd Davidson To avoid immune-mediated pathology and unrestricted , foetal–maternal tolerance and clonal expansion of responder T cells, the immune even obesity. Defects in TReg cell function may be an system has subsets of T cells, known as regulatory T important factor in the development of (TReg) cells, that are dedicated to mediating immune or in the failure to control immunopathology, whereas suppression. The most important subset of TReg cells overactive TReg cell function may contribute to the expresses the factor forkhead box P3 suppression of tumour . Enhancement of TReg (FOXP3). Both mice and humans with genetic cell function either pharmacologically or by cell-based deficiencies of FOXP3 develop severe abnormalities of therapy may prove to be an adjunct to the treatment of immune . TReg cells modulate the immune autoimmunity, whereas deletion or inactivation of TReg response in numerous settings, including autoimmune cell function may facilitate the generation of tumour disease, , microbial , tumour immunity, immunity or enhance responses to weak vaccines. Document #29957 | Version 1.2.0

Development and phenotype of regulatory T cells Function of FOXP3+ regulatory T cells + Many types have immune regulatory function, but the two most important TReg cell subsets express the transcription FOXP3 TReg cells have been shown to influence the outcome of immune responses in several tissues. For example, in the factor FOXP3 and develop in the or can be induced in peripheral sites including the mucosa-associated lymphoid intestine TReg cells have a key role in maintaining tissue homeostasis by inhibiting the overactivation of dendritic cells (DCs) and tissue (MALT). Although expression of FOXP3 is considered a useful marker for these cell subpopulations in mice, FOXP3 effector T cells. In the case of autoimmunity, such as that depicted in the central nervous system (CNS), TReg cells can have a beneficial + expression may also be induced in human T cells that lack TReg cell function. However, functional activated human FOXP3 effect by short circuiting the inflammatory loop of T cells and -presenting cells (APCs). This same general mechanism can TReg cells express a unique pattern of cell surface markers that can facilitate their isolation. A third important type of TReg cell have negative consequences in the setting of a tumour, in which TReg cells can inhibit the antitumour , thereby + secretes the immunosuppressive -10 (IL-10) and may develop from conventional CD4 T cells by activation in preventing tumour clearance. During infection TReg cells carry out a delicate balancing act; preventing immunity would lead to the the presence of IL-10 or may develop from T helper 1 (TH1) or TH2 cell subsets. Other T cell subpopulations including natural killer T inability to clear the pathogen, whereas unrestrained immunity would lead to unwanted immune-mediated tissue destruction. + + (NKT) cells, γδ T cells and CD8 T cells can also exert potent suppressor functions in certain settings. Although both human In each of the examples shown, we focus on the role of FOXP3 TReg cells, although interactions between multiple immune and mouse CD8+ T cells can be induced to express FOXP3, a suppressive function for these cells in vivo has yet to be clarified. cell types and indeed different types of are also likely to be important in the regulation of immune responses. 6J[OWU 2TGXGPVKPICWVQKOOWPKV[ FOXP3+IL-10– Regulation IL-2Rα MHC IFNγ TReg cells in (CD25) TH1 or class II T 17 cell the periphery CTLA4 H IL-17 + Uncommitted CD4 CNS thymocyte FOXP3+ FOXP3+ CD28 TCR autoantigen Antigen Self- Activation presentation MHC Damage TReg cell reactive CD4+FOXP3+ class II to the CNS recruitment TCR Unknown IL-2 or Thymic epithelial natural TReg cell antigen IL-15? cell or DC DC CD8+ thymocyte CD4+ thymocyte Damage IL-10 FOXP3+ 2GTKRJGT[ recruitment to the CNS /#.6 FOXP3+IL-10+ TReg cell TH1 and TH17 cells Resolution of IL-10 Natural APC + FOXP3+ in the periphery inflammation CD4 TR1 T cell IL-10 Reg TGFβ, Naive Naive IL-10-secreting CD8+ CD4+ IL-2, RA TGFβ + 'UVCDNKUJKPIEJTQPKEKPHGEVKQP T cell T cell CD4 TReg cell β Hepatocyte TGF CD4+ CD4+ Naive Low dose antigen, T cell TGFβ, IL-2 Naive T cell Hepatitis B IL-6, TH17 Induced or C Naive TGFβ TReg cell γδ T cell NKT cell Type I IFNs T cell FOXP3+/– FOXP3+ FOXP3+ T 3 + H MHC IL-4 FOXP3 TGFβ CD4+ T 2 class II H FOXP3+ + CD4+FOXP3+ CD4+FOXP3+ TGFβ-secreting CD8 TReg cell Infected + induced T cell FOXP3 Reg induced TReg cell TReg cell T 3 cell T 1 cell H R tissue IL-12 Natural T cell DC MHC T 1 Reg Plasticity in the periphery H class I Naive + Under certain conditions, FOXP3 TReg cells can Lethal infection, TH1 cell TReg cell -derived T cell T cell highly polarized FH CD8+ downregulate their expression of FOXP3, lose signals in Pathogen suppressor functions and manifest some of the TH1 cell response Peyer’s patch FOXP3– FOXP3+ FOXP3– persistence Autoimmune functions of conventional effector TH1, TH2, TH17 CTL and T cell subsets. The key causes of this loss microenvironment FH IL-6, Restricted of FOXP3 expression include inflammatory a tissue IL-10 IFNγ ) IL-1, FOXP3+ IL-21 CTL environments with high levels of that IL-23 IRF4– damage are normally involved in the induction of effector in vitro Lymphopeni TH2 cell T cells, such as IL-6 and - (IFN ). In γ γ (IL-2 deficiency /CKPVCKPKPIKPVGUVKPCNJQOGQUVCUKU addition, TReg cell-specific deletion of certain FOXP3– FOXP3– T 17 cell FOXP3– transcription factors that are shared between H Antigen Gut lumen Commensal bacteria TLR TReg cells and effector cell subsets (for example, the ligand T 2 cell-specific factor IRF4) results in impaired IEC H IFNγ, IL-17, IL-21 IL-17 IL-4, IL-5 suppression of TH2 cell responses by the TReg cells. 2JGPQV[RKEOCTMGTUQH(1:2 TGIWNCVQT[6EGNNU M cell

+ Markers shared by FOXP3 TReg cells Markers preferentially expressed by Markers specifically expressed by + + + and conventional activated CD4 activated mouse FOXP3 TReg cells activated human FOXP3 TReg cells hi TGFβ RA T cells (mice and humans) FOXP3 Latent TGFβ FOXP3 CD103+ DC Inflammatory DC CD25 CD127low CD103 Latent TGFβ GITR CTLA4 GARP low + CD45RB (mice only) Subpopulations of human FOXP3 TReg cells CD121a (IL-1R1) TGFβ, RA, IL-2 IL-12, IL-6, IL-23 CD45RO (humans only) CD45RA+FOXP3low (naive) CD121b (IL-1R2) Folate 4 (mice only) CD45RA–FOXP3hi (activated) CD45RA–FOXP3low (cytokine-secreting) FOXP3+ CD4+ CD4+ TGFβ, /GEJCPKUOUQHCEVKQPQH(1:2 TGIWNCVQT[6EGNNU IL-10? TReg cell Naive Naive Suppressive cytokines and secreted molecules Cytolysis T cell T cell Perforin Granzyme A Membrane- Contact-dependent pore or FOXP3+ FOXP3– tethered TGFβ inhibition IL-10, TGFβ Cell cycle arrest Lamina propria TGFβ TReg cell TH1 or TH17 cell + TReg cell FOXP3 IL-35 IL-10 CD4+ or CD8+ Granzymes effector T cell 2TQOQVKPIVWOQWTRTQITGUUKQP CD4+ or CD8+ FOXP3+ and perforin 1 IL-10 effector T cell Tumour-associated or DC IDO + Activation + CD45 CD43 TReg cell TReg cell FOXP3 CD4 Effector T cells TGFβ CCR4 + Apoptosis Co-stimulation blockade CCL22 FOXP3+ CD8+ CD8 DC Recruitment Control of tumour Metabolic disruption Targeting DCs by other mechanisms Tryptophan Proliferation FOXP3+ catabolites Co-stimulation IDO Apoptosis blockade FOXP3+ Tryptophan CD80 or CD86 depletion Increased ? FOXP3+ TGFβ, interaction TGFβ IL-10 CTLA4 MHC CD80 or Transendocytosis Inhibition of with DCs CD86 CD4+ CD39 A R class II of CD80/CD86 2A DC maturation T cell TGFβ TReg cell FOXP3+ TCR CTLA4 and decreased CD73 T cell activation DC FOXP3+ Inhibition of Conversion DC maturation IL-2Rα LAG3 (CD25) Apoptosis owing to T cell Tumour cell cytokine deprivation Reg FOXP3+ Neuropilin 1 MHC class II IL-2 molecule

Affiliations STEMCELL Technologies Ethan Shevach and Todd Davidson are at the Our EasySep™ Human CD4+CD127lowCD25+ Regulatory T Cell Isolation Immune Cell Separation Isolation of Regulatory T Cells Laboratory of , National Institute of Kit allows for fast and easy isolation of highly purified, magnetic Our portfolio of immune cell isolation products provides fast and easy Allergy and Infectious Diseases, National Institutes Regulatory T cells (Tregs) comprise only a small fraction of total particle-free Tregs in under an hour from PBMCs or leukapheresis methods to isolate subsets of immune cells from a variety of sample of Health, Bethesda, Maryland 20892, USA. CD4+ T cells in human peripheral and mouse , and samples. First, CD25+ cells are isolated by column-free immunomagnetic e-mail: [email protected] sources in as little as 8 minutes. Isolate cells from PBMCs, whole blood therefore must be highly enriched to evaluate their suppressive positive selection using EasySep™ Releasable RapidSpheres™. Then, or mouse using a wide range of EasySep™ magnets or the fully The authors declare no competing financial interests. function and therapeutic potential. Since Tregs lack a unique cell bound magnetic particles are removed from the EasySep™-isolated automated cell separation instrument, RoboSep™. surface marker and often share phenotypic similarities with CD25+ cells, and unwanted non-Tregs are targeted for depletion. Edited by Lucy Bird and Kirsty Minton; copyedited activated T cells, isolation of highly purified Tregs is typically Isolated Tregs express high levels of FOXP3, and are suitable for by Gemma Ryan; designed by Simon Bradbrook. difficult and time consuming, often requiring multiple steps. immediate downstream experiments, including flow cytometry, in vitro © 2018 Macmillan Publishers Ltd, part of Springer STEMCELL Technologies has developed optimized Treg isolation expansion or suppression assays. Nature. All rights reserved. kits that address these specific challenges. For more information about our complete range of cell isolation http://www.nature.com/nri/posters/tregcells Learn more about how EasySep™ works at www.EasySep.com products, please visit www.stemcell.com. ONLINE ONLY

Abbreviations for poster entitled Regulatory T cells by Ethan Shevach and Todd Davidson

A2AR, adenosine receptor 2A; CCL, CC- ligand; CCR, CC-; CTL, cytotoxic T ; CTLA4, cytotoxic T lymphocyte antigen 4; GARP, A repetitions predominant (also known as LRRC32); GITR, -induced TNF-receptor-related protein; IDO, indoleamine 2,3-dioxygenase; IEC, intestinal epithelial cell; IRF4, interferon-regulatory factor 4; LAG3, lymphocyte activation gene 3; M cell, microfold cell; PBMC, peripheral blood mononuclear cell; R, receptor; RA, retinoic acid; TCR; T cell receptor; TFH cell, T follicular helper cell; TGFβ, transforming growth factor-β; TLR, Toll-like receptor; TR1 cell, inducible regulatory type 1 T cell.