Phenotypic and Functional Diversity in Regulatory T Cells

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Oct 11

PMID 34631704

Citations 12

Authors

Louisa E Sjaastad

David L Owen

Sean I Tracy

Michael A Farrar

Affiliations

Soon will be listed here.

Abstract

The concept that a subset of T cells exists that specifically suppresses immune responses was originally proposed over 50 years ago. It then took the next 30 years to solidify the concept of regulatory T cells (Tregs) into the paradigm we understand today - namely a subset of CD4+ FOXP3+ T-cells that are critical for controlling immune responses to self and commensal or environmental antigens that also play key roles in promoting tissue homeostasis and repair. Expression of the transcription factor FOXP3 is a defining feature of Tregs, while the cytokine IL2 is necessary for robust Treg development and function. While our initial conception of Tregs was as a monomorphic lineage required to suppress all types of immune responses, recent work has demonstrated extensive phenotypic and functional diversity within the Treg population. In this review we address the ontogeny, phenotype, and function of the large number of distinct effector Treg subsets that have been defined over the last 15 years.

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References

Yang B, Wang K, Wan S, Liang Y, Yuan X, Dong Y . TCF1 and LEF1 Control Treg Competitive Survival and Tfr Development to Prevent Autoimmune Diseases. Cell Rep. 2019; 27(12):3629-3645.e6. PMC: 6701704. DOI: 10.1016/j.celrep.2019.05.061. View

Vasanthakumar A, Chisanga D, Blume J, Gloury R, Britt K, Henstridge D . Sex-specific adipose tissue imprinting of regulatory T cells. Nature. 2020; 579(7800):581-585. PMC: 7241647. DOI: 10.1038/s41586-020-2040-3. View

Lowe M, Boothby I, Clancy S, Ahn R, Liao W, Nguyen D . Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight. 2019; 4(24). PMC: 6975275. DOI: 10.1172/jci.insight.129756. View

Oldenhove G, Bouladoux N, Wohlfert E, Hall J, Chou D, Dos Santos L . Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity. 2009; 31(5):772-86. PMC: 2814877. DOI: 10.1016/j.immuni.2009.10.001. View

Ohnmacht C, Park J, Cording S, Wing J, Atarashi K, Obata Y . MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt⁺ T cells. Science. 2015; 349(6251):989-93. DOI: 10.1126/science.aac4263. View

Kim K, Hong S, Han D, Yi J, Jung J, Yang B . Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science. 2016; 351(6275):858-63. DOI: 10.1126/science.aac5560. View

Yasuoka S, Kawanokuchi J, Parajuli B, Jin S, Doi Y, Noda M . Production and functions of IL-33 in the central nervous system. Brain Res. 2011; 1385:8-17. DOI: 10.1016/j.brainres.2011.02.045. View

Josefowicz S, Lu L, Rudensky A . Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012; 30:531-64. PMC: 6066374. DOI: 10.1146/annurev.immunol.25.022106.141623. View

Arroyo Hornero R, Hamad I, Corte-Real B, Kleinewietfeld M . The Impact of Dietary Components on Regulatory T Cells and Disease. Front Immunol. 2020; 11:253. PMC: 7047770. DOI: 10.3389/fimmu.2020.00253. View

10.

Mosmann T, Cherwinski H, Bond M, Giedlin M, Coffman R . Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. 1986. J Immunol. 2005; 175(1):5-14. View

11.

Yadav M, Louvet C, Davini D, Gardner J, Martinez-Llordella M, Bailey-Bucktrout S . Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012; 209(10):1713-22, S1-19. PMC: 3457729. DOI: 10.1084/jem.20120822. View

12.

Yang B, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M . Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 2015; 9(2):444-57. DOI: 10.1038/mi.2015.74. View

13.

Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A . Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009; 15(8):930-9. PMC: 3115752. DOI: 10.1038/nm.2002. View

14.

Kolodin D, van Panhuys N, Li C, Magnuson A, Cipolletta D, Miller C . Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab. 2015; 21(4):543-57. PMC: 4747251. DOI: 10.1016/j.cmet.2015.03.005. View

15.

Shi H, Chi H . Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity. Front Immunol. 2020; 10:2716. PMC: 6917616. DOI: 10.3389/fimmu.2019.02716. View

16.

Cosovanu C, Neumann C . The Many Functions of Foxp3 Regulatory T Cells in the Intestine. Front Immunol. 2020; 11:600973. PMC: 7606913. DOI: 10.3389/fimmu.2020.600973. View

17.

Harrison O, Linehan J, Shih H, Bouladoux N, Han S, Smelkinson M . Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science. 2018; 363(6422). PMC: 7304459. DOI: 10.1126/science.aat6280. View

18.

Hwang S, Sharma G, Verma R, Byun S, Rudra D, Im S . Inflammation-induced Id2 promotes plasticity in regulatory T cells. Nat Commun. 2018; 9(1):4736. PMC: 6226514. DOI: 10.1038/s41467-018-07254-2. View

19.

Zheng Y, Chaudhry A, Kas A, deRoos P, Kim J, Chu T . Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009; 458(7236):351-6. PMC: 2864791. DOI: 10.1038/nature07674. View

20.

Josefowicz S, Niec R, Kim H, Treuting P, Chinen T, Zheng Y . Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature. 2012; 482(7385):395-9. PMC: 3485072. DOI: 10.1038/nature10772. View