Regulatory T Cells


The study of these cells has been ongoing for over two decades, and publications about these cells have risen to over 39 000 in Pubmed alone. Regulatory T cells, which comprise mostly CD4 lymphocytes, can, as their name suggests, regulate or control immune responses elicited by a number of immune cell types. The overall goal of this regulation is the maintenance of immune self‐tolerance and the attenuation of immunological responses elicited towards a number of different stimuli, such as bacteria, viruses and foreign or neoantigens which may be encountered against either transplanted or cancerous tissue and cells.

Key Concepts

  • Regulatory T cells (Tregs) are a subset of T cells that participate in the downregulation of immune responses.
  • Tregs can develop in the thymus or in the periphery.
  • Their main role is to control autoimmune reactions and to regulate immune responses to foreign antigens.
  • The majority of Tregs are derived from CD4+ T cells.
  • They can suppress effector immune cells through direct contact, release of soluble factors and competition for IL‐2.
  • They can suppress effector immune cells in an antigen‐specific or independent manner.

Keywords: regulatory T cell (Treg); suppression; function; phenotype; therapy; defect

Figure 1. Mechanisms by which Tregs can suppress effector cells of the immune system.


Akdis CA and Akdis M (2009) Mechanisms and treatment of allergic disease in the big picture of regulatory T cells. Journal of Allergy and Clinical Immunology 123 (4): 735–746.

Barach YS, Lee JS and Zang X (2011) T cell coinhibition in prostate cancer: new immune evasion pathways and emerging therapeutics. Trends in Molecular Medicine 17: 47–55.

Benson MJ, Pino‐Lagos K, Rosemblatt M and Noelle RJ (2007) All‐trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co‐stimulation. The Journal of Experimental Medicine 204 (8): 1765–1774.

Bilate AM and Lafaille JJ (2012) Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annual Review of Immunology 30 (1): 733–758.

Buchbinder EI and Desai A (2016) CTLA‐4 and PD‐1 pathways: similarities, differences, and implications of their inhibition. American Journal of Clinical Oncology, 39: p. 98–106. Publish Ahead of Print.

Burt TD (2013) Fetal regulatory T cells and peripheral immune tolerance in utero: implications for development and disease. American Journal of Reproductive Immunology (New York, N.Y.: 1989) 69 (4): 346–358.

Caramalho Í, Nunes‐Cabaço H, Foxall RB and Sousa AE (2015) Regulatory T‐cell development in the human thymus. Frontiers in Immunology 6: 395.

Chen L and Flies DB (2013) Molecular mechanisms of T cell co‐stimulation and co‐inhibition. Nature Reviews. Immunology 13 (4): 227–242.

Chen W and Konkel JE (2015) Development of thymic Foxp3+ regulatory T cells: TGF‐β matters. European Journal of Immunology 45 (4): 958–965.

Collison LW, Chaturvedi V, Henderson AL, et al. (2010) Interleukin‐35‐mediated induction of a novel regulatory T cell population. Nature Immunology 11 (12): 1093–1101.

Corthay A (2009) How do regulatory T cells work? Scandinavian Journal of Immunology 70 (4): 326–336.

Dhamne C, Chung Y, Alousi AM, Cooper LJN and Tran DQ (2013) Peripheral and thymic Foxp3(+) regulatory T cells in search of origin, distinction, and function. Frontiers in Immunology 4: 253.

Francisco LM, Salinas VH, Brown KE, et al. (2009) PD‐L1 regulates the development, maintenance, and function of induced regulatory T cells. The Journal of Experimental Medicine 206 (13): 3015–3029.

Grant CR, Liberal R, Mieli‐Vergani G, Vergani D and Longhi MS (2015) Regulatory T‐cells in autoimmune diseases: challenges, controversies and—yet—unanswered questions. Autoimmunity Reviews 14 (2): 105–116.

Grossman WJ, Verbsky JW, Barchet W, et al. (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21 (4): 589–601.

Han D, Wang C, Lou W, et al. (2010) Allergen‐specific IL‐10‐secreting type I T regulatory cells, but not CD4+CD25+Foxp3+ T cells, are decreased in peripheral blood of patients with persistent allergic rhinitis. Clinical Immunology 136 (2): 292–301.

Han G, Chen G, Shen B and Li Y (2013) Tim‐3: an activation marker and activation limiter of innate immune cells. Frontiers in Immunology 4.

Höfer T, Krichevsky O and Altan‐Bonnet G (2012) Competition for IL‐2 between regulatory and effector T cells to chisel immune responses. Frontiers in Immunology 3: 268.

Horwitz DA, Zheng SG, Wang J and Gray JD (2008) Critical role of IL‐2 and TGF‐beta in generation, function and stabilization of Foxp3+CD4+ Treg. European Journal of Immunology 38 (4): 912–915.

Huan J, Culbertson N, Spencer L, et al. (2005) Decreased FOXP3 levels in multiple sclerosis patients. Journal of Neuroscience Research 81 (1): 45–52.

Josefowicz SZ, Niec RE, Kim HY, et al. (2012) Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482 (7385): 395–399.

Karim M, Kingsley CI, Bushell AR, Sawitzki BS and Wood KJ (2004) Alloantigen‐induced CD25+CD4+ regulatory T cells can develop in vivo from CD25−CD4+ precursors in a thymus‐independent process. The Journal of Immunology 172 (2): 923–928.

Kemper C, Chan AC, Green JM, et al. (2003) Activation of human CD4+ cells with CD3 and CD46 induces a T‐regulatory cell 1 phenotype. Nature 421 (6921): 388–392.

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LeMercier I, Chen W, Lines JL, et al. (2014) VISTA regulates the development of protective anti‐tumor immunity. Cancer Research 74 (7): 1933–1944.

Li Y‐Q, Liu F‐F, Zhang X‐M, et al. (2013) Tumor secretion of CCL22 activates intratumoral Treg infiltration and is independent prognostic predictor of breast cancer. PloS One 8 (10): e76379.

Lozano E, Dominguez‐Villar M, Kuchroo V and Hafler DA (2012) The TIGIT/CD226 axis regulates human T cell function. The Journal of Immunology 188 (8): 3869–3875.

Mailloux AW and Young MRI (2010) Regulatory T‐cell trafficking: from thymic development to tumor‐induced immune suppression. Critical Reviews in Immunology 30 (5): 435–447.

Mandapathil M, Szczepanski MJ, Szajnik M, et al. (2010) Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. Journal of Biological Chemistry 285 (36): 27571–27580.

Nizar S, Copier J, Meyer B, et al. (2009) T‐regulatory cell modulation: the future of cancer immunotherapy? British Journal of Cancer 100 (11): 1697–1703.

Peterson RA (2012) Regulatory T‐cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicologic Pathology 40 (2): 186–204.

Petrich de Marquesini LG, Fu J, Connor KJ, et al. (2010) IFN‐γ and IL‐10 islet‐antigen‐specific T cell responses in autoantibody‐negative first‐degree relatives of patients with type 1 diabetes. Diabetologia 53 (7): 1451–1460.

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Robinson DS (2009) Regulatory T cells and asthma. Clinical & Experimental Allergy 39 (9): 1314–1323.

Safinia N, Leech J, Hernandez‐Fuentes M, Lechler R and Lombardi G (2013) Promoting transplantation tolerance; adoptive regulatory T cell therapy. Clinical & Experimental Immunology 172 (2): 158–168.

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Sehrawat S and Rouse BT (2011) Tregs and infections: on the potential value of modifying their function. Journal of Leukocyte Biology 90 (6): 1079–1087.

Sharma P and Allison JP (2015) The future of immune checkpoint therapy. Science 348 (6230): 56–61.

Tran DQ (2012) TGF‐β: the sword, the wand, and the shield of FOXP3+ regulatory T cells. Journal of Molecular Cell Biology 4 (1): 29–37.

Verhagen J, Wegner A and Wraith DC (2015) Extra‐thymically induced T regulatory cell subsets: the optimal target for antigen‐specific immunotherapy. Immunology 145 (2): 171–181.

Wang Y, Liu XP, Zhao ZB, Chen JH and Yu CG (2011) Expression of CD4+ forkhead box P3 (FOXP3)+ regulatory T cells in inflammatory bowel disease. Journal of Digestive Diseases 12 (4): 286–294.

Whiteside TL (2012) What are regulatory T cells (Treg) regulating in cancer and why? Seminars in Cancer Biology 22 (4): 327–334.

Wirtz S, Billmeier U, McHedlidze T, Blumberg RS and Neurath MF (2011) Interleukin‐35 mediates mucosal immune responses that protect against T‐cell‐dependent colitis. Gastroenterology 141 (5): 1875–1886.

Zeng H, Zhang R, Jin B and Chen L (2015) Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cellular & Molecular Immunology 12 (5): 566–571.

Zhang H, Kong H, Zeng X, et al. (2014) Subsets of regulatory T cells and their roles in allergy. Journal of Translational Medicine 12: 125.

Further Reading

Akdis M, Verhagen J, Taylor A, et al. (2004) Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen‐specific T regulatory 1 and T helper 2 cells. The Journal of Experimental Medicine 199 (11): 1567–1575.

Badami E, Sorini C, Coccia M, et al. (2011) Defective differentiation of regulatory FoxP3+ T cells by small‐intestinal dendritic cells in patients with type 1 diabetes. Diabetes 60 (8): 2120–2124.

Garín MI, Chu C‐C, Golshayan D, et al. (2006) Galectin‐1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109 (5): 2058–2065.

Gärtner D, Hoff H, Gimsa U, Burmester G‐R and Brunner‐Weinzierl MC (2006) CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long‐term disease progression. Journal of Neuroimmunology 172 (1–2): 73–84.

Ishigame H, Zenewicz LA, Sanjabi S, et al. (2013) Excessive Th1 responses due to the absence of TGF‐β signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Proceedings of the National Academy of Sciences of the United States of America 110 (17): 6961–6966.

Luckey U, Schmidt T, Pfender N, et al. (2012) Crosstalk of regulatory T cells and tolerogenic dendritic cells prevents contact allergy in subjects with low zone tolerance. Journal of Allergy and Clinical Immunology 130 (3): 781–797.e711.

Motz GT, Santoro SP, Wang L‐P, et al. (2014) Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nature Medicine 20 (6): 607–615.

Oldenhove G, Bouladoux N, Wohlfert EA, et al. (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31 (5): 772–786.

Ren X, Ye F, Jiang Z, et al. (2007) Involvement of cellular death in TRAIL//DR5‐dependent suppression induced by CD4+CD25+ regulatory T cells. Cell Death and Differentiation 14 (12): 2076–2084.

Tran DQ, Glass DD, Uzel G, et al. (2009) Analysis of adhesion molecules, target cells, and role of IL‐2 in human FOXP3+ regulatory T cell suppressor function. The Journal of Immunology 182 (5): 2929–2938.

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Galustian, Christine, and Dasgupta, Prokar(Apr 2016) Regulatory T Cells. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0004029.pub3]