IL-17+ Regulatory T Cells in the Microenvironments of Chronic Inflammation and Cancer

Foxp3+CD4+ regulatory T (Treg) cells inhibit immune responses and temper inflammation. IL-17+CD4+ T (Th17) cells mediate inflammation of autoimmune diseases. A small population of IL-17+Foxp3+CD4+ T cells has been observed in peripheral blood in healthy human beings. However, the biology of IL-17+Foxp3+CD4+ T cells remains poorly understood in humans. We investigated their phenotype, cytokine profile, generation, and pathological relevance in patients with ulcerative colitis. We observed that high levels of IL-17+Foxp3+CD4+ T cells were selectively accumulated in the colitic microenvironment and associated colon carcinoma. The phenotype and cytokine profile of IL-17+Foxp3+CD4+ T cells was overlapping with Th17 and Treg cells. Myeloid APCs, IL-2, and TGF-β are essential for their induction from memory CCR6+ T cells or Treg cells. IL-17+Foxp3+CD4+ T cells functionally suppressed T cell activation and stimulated inflammatory cytokine production in the colitic tissues. Our data indicate that IL-17+Foxp3+ cells may be “inflammatory” Treg cells in the pathological microenvironments. These cells may contribute to the pathogenesis of ulcerative colitis through inducing inflammatory cytokines and inhibiting local T cell immunity, and in turn may mechanistically link human chronic inflammation to tumor development. Our data therefore challenge commonly held beliefs of the anti-inflammatory role of Treg cells and suggest a more complex Treg cell biology, at least in the context of human chronic inflammation and associated carcinoma.

[1]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[2]  Jay K Kolls,et al.  The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation , 2022 .

[3]  M. Merino,et al.  FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions. , 2008, Blood.

[4]  A. Lindén,et al.  Interleukin-17 family members and inflammation. , 2004, Immunity.

[5]  M. Roncarolo,et al.  IL-10 and TGF-beta induce alloreactive CD4+CD25- T cells to acquire regulatory cell function. , 2003, Blood.

[6]  W. Zou.  Regulatory T cells, tumour immunity and immunotherapy , 2006, Nature Reviews Immunology.

[7]  Hiromu Ito,et al.  Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model , 2007, The Journal of experimental medicine.

[8]  A. Baird,et al.  Tissue cytokine and chemokine expression in inflammatory bowel disease , 2001, Inflammation Research.

[9]  R. Grencis.  Faculty Opinions recommendation of Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. , 2005 .

[10]  S. Sakaguchi.  Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self , 2005, Nature Immunology.

[11]  A. Andoh,et al.  IL-17 stimulates inflammatory responses via NF-kappaB and MAP kinase pathways in human colonic myofibroblasts. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[12]  T. Wynn.  TH-17: a giant step from TH1 and TH2 , 2005, Nature Immunology.

[13]  F. Pallone,et al.  Mechanisms of tissue damage in inflammatory bowel disease , 2001, Current opinion in gastroenterology.

[14]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[15]  W. Sandborn,et al.  Inflammatory bowel disease: clinical aspects and established and evolving therapies , 2007, The Lancet.

[16]  Ethan M. Shevach,et al.  CD4+CD25+ suppressor T cells: more questions than answers , 2002, Nature Reviews Immunology.

[17]  R. D. Hatton,et al.  Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective , 2009, Nature Reviews Immunology.

[18]  S. Nakae,et al.  IL-17 Plays an Important Role in the Development of Experimental Autoimmune Encephalomyelitis1 , 2006, The Journal of Immunology.

[19]  N. Tubridy,et al.  CD39+Foxp3+ Regulatory T Cells Suppress Pathogenic Th17 Cells and Are Impaired in Multiple Sclerosis1 , 2009, The Journal of Immunology.

[20]  W. Zou,et al.  Cutting Edge: Opposite Effects of IL-1 and IL-2 on the Regulation of IL-17+ T Cell Pool IL-1 Subverts IL-2-Mediated Suppression1 , 2007, The Journal of Immunology.

[21]  A. Zinsmeister,et al.  Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival , 2000, Gut.

[22]  Gefeng Zhu,et al.  B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma , 2006, The Journal of experimental medicine.

[23]  C. Tato,et al.  Immunology: What does it mean to be just 17? , 2006, Nature.

[24]  G. Eberl,et al.  DC activated via dectin-1 convert Treg into IL-17 producers , 2008, European journal of immunology.

[25]  D. Littman,et al.  Identification of IL-17-producing FOXP3+ regulatory T cells in humans , 2009, Proceedings of the National Academy of Sciences.

[26]  K. Abrams,et al.  The risk of colorectal cancer in ulcerative colitis: a meta-analysis , 2001, Gut.

[27]  K. Murphy,et al.  Th17: an effector CD4 T cell lineage with regulatory T cell ties. , 2006, Immunity.

[28]  L. Cosmi,et al.  Human interleukin 17–producing cells originate from a CD161+CD4+ T cell precursor , 2008, The Journal of experimental medicine.

[29]  W. Strober,et al.  Cutting Edge: Regulatory T Cells Induce CD4+CD25−Foxp3− T Cells or Are Self-Induced to Become Th17 Cells in the Absence of Exogenous TGF-β , 2007, The Journal of Immunology.

[30]  M. Banerjee,et al.  Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. , 2009, Blood.

[31]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[32]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[33]  L. Coussens,et al.  CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. , 2009, Cancer cell.

[34]  M. Banerjee,et al.  Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma. , 2007, Cancer research.

[35]  W. Zou,et al.  TH17 cells in tumour immunity and immunotherapy , 2011, Nature Reviews Immunology.

[36]  James T. Elder,et al.  Induction of IL-17+ T Cell Trafficking and Development by IFN-γ: Mechanism and Pathological Relevance in Psoriasis1 , 2008, The Journal of Immunology.

[37]  W. Zou,et al.  TH17 cells in tumour immunity and immunotherapy , 2010, Nature Reviews Immunology.

[38]  A. Chang,et al.  FOXP3 defines regulatory T cells in human tumor and autoimmune disease. , 2009, Cancer research.

[39]  A. Munakata,et al.  The role of proinflammatory and immunoregulatory cytokines in the pathogenesis of ulcerative colitis. , 1995, Journal of gastroenterology.

[40]  J. Lötvall,et al.  Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. , 1999, Journal of immunology.

[41]  Yuelei Shen,et al.  TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function , 2008, Nature.

[42]  Cara H Olsen,et al.  Review of the Use of Statistics inInfection andImmunity , 2003, Infection and Immunity.

[43]  Weiping Zou,et al.  Immunosuppressive networks in the tumour environment and their therapeutic relevance , 2005, Nature Reviews Cancer.

[44]  David A. Price,et al.  Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover , 2007, The Journal of experimental medicine.

[45]  Irma Joosten,et al.  Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. , 2008, Blood.

[46]  C. Baecher-Allan,et al.  IL-17-producing human peripheral regulatory T cells retain suppressive function. , 2009, Blood.

[47]  K. Mills,et al.  A crucial role for interleukin (IL)-1 in the induction of IL-17–producing T cells that mediate autoimmune encephalomyelitis , 2006, The Journal of experimental medicine.

[48]  Danila Valmori,et al.  Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt , 2009, Proceedings of the National Academy of Sciences.

[49]  H. Spits,et al.  Generation and Maintenance of Cloned Human T Cell Lines , 2005, Current protocols in immunology.

[50]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[51]  Mario Roederer,et al.  Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses , 2007, The Journal of experimental medicine.

[52]  S. Carding,et al.  Inflammatory bowel disease: cause and immunobiology , 2007, The Lancet.

[53]  Leonard C. Harrison,et al.  Regulatory lymphocytes: Antigen-induced regulatory T cells in autoimmunity , 2003, Nature Reviews Immunology.

[54]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[55]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[56]  嶋田 光恵.  IL-6 secretion by human pancreatic periacinar myofibroblasts in response to inflammatory mediators , 2002 .

[57]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[58]  C. Dong.  Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells , 2006, Nature Reviews Immunology.

[59]  Hiroshi Sato,et al.  Cooperation of interleukin‐17 and interferon‐γ on chemokine secretion in human fetal intestinal epithelial cells , 2001, Clinical and experimental immunology.