Review Article | Published:

Regulatory T cells in nonlymphoid tissues

Nature Immunology volume 14, pages 10071013 (2013) | Download Citation


Both Foxp3+CD4+ regulatory T cells (Treg cells) and local immune responses in nonlymphoid tissues have long been recognized as important elements of a well-orchestrated immune system, but only recently have these two fields of study begun to intersect. There is growing evidence that Treg cells are present in various nonlymphoid tissues in health and disease, that they have a unique phenotype and that their functions go beyond the classical modulation of immune responses. Thus, tissue Treg cells might add yet another level to classification of the Treg cell compartment into functional and/or phenotypic subtypes. In this Review, we summarize recent findings in this new field, discussing knowns and unknowns about the origin, phenotype, function and memory of nonlymphoid tissue-resident Treg cells.

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  1. 1.

    , , & Cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).

  2. 2.

    , , & Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat. Immunol. 10, 689–695 (2009).

  3. 3.

    et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458, 351–356 (2009).

  4. 4.

    et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).In references 3 and 4, the concept is introduced that Treg cells adapt their phenotype to match the type of immune response they are controlling, sometimes sharing key segments of the transcriptional program with co-residing T effector cells.

  5. 5.

    et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

  6. 6.

    et al. The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37, 511–523 (2012).

  7. 7.

    et al. An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes. Immunity 36, 731–741 (2012).

  8. 8.

    et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).

  9. 9.

    et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).

  10. 10.

    et al. T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 37, 501–510 (2012).

  11. 11.

    et al. Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. J. Exp. Med. 204, 1335–1347 (2007).This report described the homing receptor expression and tissue localization of Treg cells in the steady state, and showed that impairing Treg cell migration to nonlymphoid tissues results in the development of tissue-specific inflammatory disease.

  12. 12.

    et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).This study reported for the first time the presence of a unique population of Treg cells in male visceral adipose tissue and their role in controlling metabolic parameters.

  13. 13.

    , , & CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479–1489 (2004).

  14. 14.

    , , & Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum. 56, 509–520 (2007).

  15. 15.

    et al. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J. Exp. Med. 203, 777–788 (2006).

  16. 16.

    et al. Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J. Exp. Med. 201, 1037–1044 (2005).

  17. 17.

    et al. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150, 29–38 (2012).This work demonstrated that peripheral Treg cells specific for paternal antigens accumulate in the placenta and prevent fetal resorption, and suggested that extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance.

  18. 18.

    et al. Evidence for a selective migration of fetus-specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J. Immunol. 180, 5737–5745 (2008).

  19. 19.

    et al. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron. 6, 147–157 (2013).

  20. 20.

    et al. Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions. PLoS ONE 2, e779 (2007).

  21. 21.

    et al. Statins induce the accumulation of regulatory T cells in atherosclerotic plaque. Mol. Med. 18, 598–605 (2012).

  22. 22.

    , & Differentiation and function of Foxp3(+) effector regulatory T cells. Trends Immunol. 34, 74–80 (2013).

  23. 23.

    et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).This report identified PPAR-γ as a crucial molecular orchestrator of the accumulation, phenotype and function of Treg cells in male visceral adipose tissue, demonstrating that a specific transcription factor can drive the unique characteristics of a particular tissue Treg population.

  24. 24.

    & Fat and beyond: the diverse biology of PPARgamma. Annu. Rev. Biochem. 77, 289–312 (2008).

  25. 25.

    , & Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. (18 September 2013) .

  26. 26.

    , & Basic principles of tumor-associated regulatory T cell biology. Trends Immunol. 34, 33–40 (2013).

  27. 27.

    et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res. 69, 2000–2009 (2009).

  28. 28.

    et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS ONE 7, e30676 (2012).

  29. 29.

    et al. Tumor-infiltrating regulatory T cells delineated by upregulation of PD-1 and inhibitory receptors. Cell. Immunol. 278, 76–83 (2012).

  30. 30.

    et al. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-beta1 mediates suppression in the tumor microenvironment. Clin. Cancer Res. 13, 4345–4354 (2007).

  31. 31.

    et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).This study demostrated that Treg cells have an immunopathological role in human cancer by showing that they accumulate in ovarian tumors, recruited by CCL22, and that they suppress antitumoral T cell responses.

  32. 32.

    et al. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J. Immunol. 182, 1746–1755 (2009).

  33. 33.

    et al. Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J. Exp. Med. 205, 2125–2138 (2008).

  34. 34.

    et al. Intratumoral convergence of the TCR repertoires of effector and Foxp3+ CD4+ T cells. PLoS ONE 5, e13623 (2010).

  35. 35.

    et al. Tumor evasion of the immune system by converting CD4+. J. Immunol. 178, 2883–2892 (2007).

  36. 36.

    , & Regulatory T cell migration during an immune response. Trends Immunol. 33, 174–180 (2012).

  37. 37.

    et al. Dynamic development of homing receptor expression and memory cell differentiation of infant CD4+CD25high regulatory T cells. J. Immunol. 183, 4360–4370 (2009).

  38. 38.

    & Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat. Rev. Immunol. 11, 119–130 (2011).

  39. 39.

    et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity 30, 458–469 (2009).This report described the migration pattern of Treg cells in a model of islet transplantation and proposed that Treg cells, to efficiently control an alloimmune response, need to be educated first in the target tissue before entering the draining lymph node.

  40. 40.

    et al. Response to self antigen imprints regulatory memory in tissues. Nature 480, 538–542 (2011).

  41. 41.

    et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).This work identified an endogenous population of thymus-derived Treg cells that infiltrates mouse prostate tumors and is specific for a normal prostate antigen, and demonstrated that Aire-mediated expression of peripheral-tissue antigens can drive the generation of tissue-specific Treg cell subsets.

  42. 42.

    & Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu. Rev. Immunol. 30, 733–758 (2012).

  43. 43.

    et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

  44. 44.

    et al. A central role for induced regulatory T cells in tolerance induction in experimental colitis. J. Immunol. 182, 3461–3468 (2009).

  45. 45.

    et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).This study demonstrated that a cocktail of Clostridia species, a component of the mammalian colonic microbiota, promote anti-inflammatory immune responses by expanding and activating Treg cells in the colonic lamina propria.

  46. 46.

    et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010).

  47. 47.

    et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010).

  48. 48.

    et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).This paper showed that mice deficient in peripheral Treg cells spontaneously develop pronounced TH2 cell–type pathologies at mucosal sites and have altered gut microbial communities, demostrating the functional specialization of peripheral Treg cells and confirming that thymus-derived Treg cells are the major controllers of systemic and tissue-specific autoimmunity.

  49. 49.

    et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

  50. 50.

    et al. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance. J. Exp. Med. 210, 775–788 (2013).

  51. 51.

    , , & Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat. Med. 12, 518–525 (2006).

  52. 52.

    & Natural regulatory T cells and de novo–induced regulatory T cells contribute independently to tumor-specific tolerance. J. Immunol. 178, 2155–2162 (2007).

  53. 53.

    et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

  54. 54.

    et al. Visceral adipose inflammation in obesity is associated with critical alterations in T regulatory cell numbers. PLoS ONE 6, e16376 (2011).

  55. 55.

    et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc. Natl. Acad. Sci. USA 107, 9765–9770 (2010).

  56. 56.

    et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 24, 5373–5380 (2006).

  57. 57.

    et al. Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer. Eur. J. Cancer 44, 1875–1882 (2008).

  58. 58.

    et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073–1081 (2009).

  59. 59.

    , & Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

  60. 60.

    , , & The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin. Cancer Res. 18, 3022–3029 (2012).

  61. 61.

    , & Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol. Immunother. 60, 909–918 (2011).

  62. 62.

    et al. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes 60, 2954–2962 (2011).

  63. 63.

    et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192–199 (2009).

  64. 64.

    et al. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood 121, 679–691 (2013).

  65. 65.

    et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med. 12, 178–180 (2006).

  66. 66.

    et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J. Clin. Invest. 123, 1323–1334 (2013).

  67. 67.

    et al. Regulatory T cells ameliorate cardiac remodeling after myocardial infarction. Basic Res. Cardiol. 107, 232 (2012).

  68. 68.

    et al. Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis. J. Immunol. 187, 1150–1156 (2011).

  69. 69.

    , & Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

  70. 70.

    Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

  71. 71.

    et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475, 226–230 (2011).

  72. 72.

    et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).

  73. 73.

    , , & The development and function of memory regulatory T cells after acute viral infections. J. Immunol. 189, 2805–2814 (2012).

  74. 74.

    et al. Antigen-specific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection. J. Immunol. 190, 3438–3446 (2013).

  75. 75.

    & IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood 109, 194–202 (2007).

  76. 76.

    et al. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873–884 (2012).

  77. 77.

    et al. The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo. J. Clin. Invest. 118, 3639–3650 (2008).

  78. 78.

    , , & Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490, 102–106 (2012).This study showed that pregnancy selectively stimulates the accumulation of maternal Treg cells with fetal specificity, which, after delivery, persist at elevated levels, maintain tolerance to preexisting fetal antigen and rapidly reaccumulate during subsequent pregnancy, demonstrating the importance of Treg cells for sustaining protective regulatory memory to fetal antigen.

  79. 79.

    Mechanisms of T cell tolerance towards the allogeneic fetus. Nat. Rev. Immunol. 13, 23–33 (2013).

  80. 80.

    , , & Alloantigen-enhanced accumulation of CCR5+ 'effector' regulatory T cells in the gravid uterus. Proc. Natl. Acad. Sci. USA 104, 594–599 (2007).

  81. 81.

    & Tolerance induction at the early maternal-placental interface through selective cell recruitment and targeting by immune polypeptides. Am. J. Reprod. Immunol. 69, 359–368 (2013).

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Work on tissue Treg cells in our laboratory is supported by US National Institutes of Health grants R01DK092541 and R37AI051530 (to C.B. and D.M.). D.B. was supported by a Kaneb Fellowship.

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  1. Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Dalia Burzyn
    • , Christophe Benoist
    •  & Diane Mathis


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The authors declare no competing financial interests.

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Correspondence to Christophe Benoist or Diane Mathis.

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