The role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer

doi:10.1016/j.clim.2013.05.003

Clinical Immunology

Volume 148, Issue 2, August 2013, Pages 246-253

https://doi.org/10.1016/j.clim.2013.05.003 Get rights and content

Highlights

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Foxp3⁺ T_Reg cells are able to express RORγt and produce IL-17.
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IL-17⁺ T_Reg cells are accumulated in the inflamed intestinal mucosa.
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IL-17⁺ T_Reg cells have potent T-cell suppressive activity.
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RORγt⁺ T_Reg cells are unable to suppress inflammation.
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IL-17⁺/RORγt⁺ T_Reg cells are pathogenic T_Reg cells with proinflammatory properties.

Abstract

The intestinal epithelium and underlying lamina propria contain T cells that play important roles in maintaining colonic homeostasis. These T cells mediate substantial and specific regulation to ensure that pathogenic microorganisms are eliminated while commensal bacteria are tolerated. There is considerable evidence supporting the notion that the altered ratio between Foxp3⁺CD4⁺ T regulatory cells and T effector cells in the colonic microenvironment might contribute to the initiation and progression of inflammation and eventually development of colon cancer. Recent findings on the heterogeneity and plasticity of T regulatory cells, such as the identification of IL-17⁺Foxp3⁺CD4⁺ and the RORγt⁺Foxp3⁺CD4⁺ subsets, in patients with colorectal inflammation and cancer have provided a new twist in our understanding of the pathogenesis of colonic diseases. Phenotypic and functional properties of IL-17-producing Foxp3⁺CD4⁺ T cells as well as the significant implications of these cells in the initiation and progression of colorectal diseases are discussed in this review.

Introduction

Regulatory T (T_Reg) cells expressing the transcription factor forkhead box P3 (Foxp3) are naturally present in the immune system. T_Reg cells suppress the activation, proliferation and effector functions of a wide range of immune cells, including CD4⁺ and CD8⁺ T cells, natural killer (NK) and NKT cells, B cells and antigen presenting cells in vitro and in vivo [1]. T_Reg cells have key roles in the prevention of autoimmune responses and the development of immunopathology as well as in the maintenance of homeostasis. As a double-edged sword, T_Reg cells can also suppress antitumor immune responses and can favor tumor progression. The unique functional properties of T_Reg cells make these cells a primary target in the search for new cell-based immunotherapeutic approaches. However, recent studies showed that T_Reg cells are not a homogeneous and terminally differentiated cell population. Instead, these cells are heterogeneous in gene expression, phenotype and function. In addition, T_Reg cells are strongly affected by other immune components including effector cells and innate immune cells during initiation and progression of disease. Thus, to achieve the translational goal of applying T_Reg cells in the treatment of diseases, understanding of the T_Reg cell immunobiology in the context of various tissues and pathogenesis of various diseases is required. Lymphocytes of mucosal tissues form a relatively autonomous immune subsystem, with specialized adaptations appropriate for this particular microenvironment [2], [3], [4]. The intestinal mucosa is normally maintained in a state of controlled inflammation in which equilibrium exists between protective immunity and tolerance to self-antigen and commensal bacteria [5]. Protective immunity against different classes of pathogens depends on the generation of distinct types of immune responses mediated and coordinated by effector cells specifically T_H1, T_H2 and T_H17. On the other hand, T_Reg cells are involved in the maintenance of tolerance. A series of observations suggests that T_Reg cells correlate with poor prognosis in many cancer types, including breast, lung, melanoma, and ovarian carcinoma [6] due to their suppressive effects on anti-tumor immunity. However, several studies have shown that T_Reg cells are protective in cancer by virtue of their ability to control inflammation in an IL-10 dependent manner [7]. In fact, Foxp3 expression has been indicative of better prognosis in gastric cancer, head and neck, and breast cancer [8], [9], [10]. Recent identification of IL-17-producing Foxp3⁺CD4⁺ T cells in IBD, colon cancer and polyposis might provide a potential explanation for the conflicting observations regarding the role of T_Reg cells in cancer. Furthermore, the advancements in understanding T_Reg immunobiology locally and systemically and the influence of inflammatory microenvironments on the differentiation of effector cells and on the stability of T_Reg cells would improve the use of T_Reg as cell-based immunotherapy.

Section snippets

Heterogeneity of T_Reg cells

Foxp3⁺CD4⁺ T_Reg cells are not homogeneous in gene expression, phenotype and suppressive function. The transcription factor Foxp3, a master control gene for the development and function of both mouse and human T_Reg cells [11], [12], [13], [14], is currently the definitive marker of T_Reg cells. However, Foxp3 can be transiently expressed in activated human T cells. This transient Foxp3 expression in T cells does not enable suppression but, instead, makes separation of T_Reg cells from activated T

Characterization of in vitro induced IL-17-producing Foxp3⁺CD4⁺ T cells

T_Reg cells are well known to produce IL-10 and TGF-β during activation and these cytokines are considered to be part of the mechanisms via which T_Reg cells mediate their suppressive function [21]. Recent findings reveal that T_Reg cells are capable of producing IL-17. There is an intimate link between T_H17 cells and T_Reg cells. Exposure of antigen-activated naïve T cells to TGF-β in vitro results in transcriptional up-regulation of both Foxp3 and RORγt [22]. Furthermore, T cells co-expressing

Roles of T_Reg cells and T_H17 cells in inflammation and colon cancer

The intestinal tract contains large numbers of immune cells involved in the encounter with microbial antigens. Under normal conditions, the lumen of the intestine is covered by a layer of intestinal epithelial cells (IECs), which are joined together by tight junctions forming a protective layer impeding bacterial invasion [34]. Immune responses in the colon take place in three distinct compartments: the lamina propria, the isolated lymphoid follicles (ILFs) scattered throughout the colon, and

Paradoxical roles of IL-17-producing Foxp3⁺CD4⁺ cells in anti-inflammatory response and anti-tumor immunity

Inflammatory and tumor tissues often have lower frequency of CD69⁺ T effector cells but a higher frequency of T_H17 cells and T_Reg cells compared to healthy or untransformed tissues [53]. The mechanisms by which T_H17 cells and T_Reg cells accumulate in such inflammatory and tumor tissues and their roles in the pathogenesis of these diseases remain unsolved. The identification of IL-17⁺Foxp3⁺ T cells in inflamed intestinal mucosa of patients with IBD and cancer but not in healthy control might

Conclusions

The immunobiology of T_Reg cells has been intensively investigated since the discovery of T_Reg cells and their master transcription factor Foxp3, more than a decade ago. Such efforts have led to significant advances in our understanding of the development of T_Reg cells and the molecular mechanisms underlying their suppression function. Recent studies have focused on understanding the reciprocal relationship between T_Reg and other immune components surrounding T_Reg cells. Through these studies it

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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^☆: This study is supported by NIH grants HL107997-01, R56AI43552 and by the Leukemia and Lymphoma Society Translational Research Program TRP 6222–11.

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ReviewThe role of IL-17-producing Foxp3+ CD4+ T cells in inflammatory bowel disease and colon cancer☆

Highlights

Abstract

Introduction

Section snippets

Heterogeneity of TReg cells

Characterization of in vitro induced IL-17-producing Foxp3+CD4+ T cells

Roles of TReg cells and TH17 cells in inflammation and colon cancer

Paradoxical roles of IL-17-producing Foxp3+CD4+ cells in anti-inflammatory response and anti-tumor immunity

Conclusions

Conflict of interest statement

Cell

Blood

Immunity

Immunity

Immunity

Blood

Semin. Immunol.

Gastroenterology

Immunity

Gastroenterology

Immunity

Cell

A common mucosal immunologic system involving the bronchus, breast and bowel

Adv. Exp. Med. Biol.

Diurnal profiles of gastrointestinal regulatory peptides

Scand. J. Gastroenterol.

T lymphocytes of the human colonic mucosa: functional and phenotypic analysis

Clin. Exp. Immunol.

Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD)

Clin. Exp. Immunol.

Treg cells in cancer: a case of multiple personality disorder

Sci. Transl. Med.

T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis

Cancer Res.

Prognostic value of tumor-infiltrating CD4 + T-cell subpopulations in head and neck cancers

Clin. Cancer Res.

Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia

BMC Gastroenterol.

Presence of Foxp3 expression in tumor cells predicts better survival in HER2-overexpressing breast cancer patients treated with neoadjuvant chemotherapy

Breast Cancer Res. Treat.

Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells

Nat. Immunol.

Control of regulatory T cell development by the transcription factor Foxp3

Science

An essential role for Scurfin in CD4 + CD25 + T regulatory cells

Nat. Immunol.

Analysis of FOXP3 protein expression in human CD4 + CD25 + regulatory T cells at the single-cell level

Eur. J. Immunol.

FOXP3 + regulatory T cells in the human immune system

Nat. Rev. Immunol.

A peripheral circulating compartment of natural naive CD4 Tregs

J. Clin. Invest.

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.

TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function

Nature

Identification of IL-17-producing FOXP3 + regulatory T cells in humans

Proc. Natl. Acad. Sci. U. S. A.

Review
The role of IL-17-producing Foxp3⁺ CD4⁺ T cells in inflammatory bowel disease and colon cancer☆

Heterogeneity of T_Reg cells

Characterization of in vitro induced IL-17-producing Foxp3⁺CD4⁺ T cells

Roles of T_Reg cells and T_H17 cells in inflammation and colon cancer

Paradoxical roles of IL-17-producing Foxp3⁺CD4⁺ cells in anti-inflammatory response and anti-tumor immunity