Exacerbating Role of γδ T Cells in Chronic Colitis of T-Cell Receptor α Mutant Mice

Nanno, Masanobu; Kanari, Yasuyoshi; Naito, Tomoaki; Inoue, Nagamu; Hisamatsu, Tadakazu; Chinen, Hiroshi; Sugimoto, Ken; Shimomura, Yoshiharu; Yamagishi, Hideo; Shiohara, Tetsuo; Ueha, Satoshi; Matsushima, Kouji; Suematsu, Makoto; Mizoguchi, Atsushi; Hibi, Toshifumi; Bhan, Atul K.; Ishikawa, Hiromichi

doi:10.1053/j.gastro.2007.11.056

Cited by 51 publications

(43 citation statements)

References 49 publications

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“…g/d T cells are crucially involved in host immune defense against infections (42) but are also known to have a strong clinical association with various autoimmune diseases such as inflammatory bowel disease (43,44), rheumatoid arthritis (or collageninduced arthritis, the murine model of rheumatoid arthritis) (45,46), and multiple sclerosis (or experimental autoimmune encephalomyelitis, the murine model of multiple sclerosis) (32,47). In addition, there is compelling evidence indicating that g/d T cells play an important role in immunity to cancer by sensing and reacting to cellular stress.…”

Section: Cd44mentioning

confidence: 99%

Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Lombès

Durand

Charvet

et al. 2015

The Journal of Immunology

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To better apprehend γ/δ T cell biological functions in the periphery, it appears crucial to identify markers highlighting the existence of distinct phenotypic and functional γ/δ T cell subsets. Interestingly, the expression of CD44 and Ly-6C subdivides murine peripheral γ/δ T cells into several subsets, with Ly-6C− CD44hi γ/δ T cells corresponding to the IL-17–producing CD27− γ/δ T cell subset exhibiting innate-like features. By comparing the other subsets to naive and memory CD8+ α/β T cells, in this study, we show that Ly-6C− or + CD44lo and Ly-6C+CD44hi γ/δ T cells greatly resemble, and behave like, their CD8+ α/β T cell counterparts. First, like memory CD8+ α/β T cells, Ly-6C+CD44hi γ/δ T cells are sparse in the thymus but largely increased in proportion in tissues. Second, similarly to naive CD8 α/β T cells, CD44lo γ/δ T cells are poorly cycling in vivo in the steady state, and their proportion declines with age in secondary lymphoid organs. Third, CD44lo γ/δ T cells undergo spontaneous proliferation and convert to a memory-like Ly-6C+CD44hi phenotype in response to lymphopenia. Finally, CD44lo γ/δ T cells have an intrinsic high plasticity as, upon appropriate stimulation, they are capable of differentiating nonetheless into Th17-like and Th1-like cells but also into fully functional Foxp3+ induced regulatory T cell–like γ/δ T cells. Thus, peripheral CD27+ γ/δ T cells, commonly considered as a functionally related T cell compartment, actually share many common features with adaptive α/β T cells, as both lineages include naive-like and memory-like lymphocytes with distinct phenotypic, functional, and homeostatic characteristics.

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Section: Cd44mentioning

confidence: 99%

Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Lombès

Durand

Charvet

et al. 2015

The Journal of Immunology

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“…Although the majority of these IELs express the γδ T cell receptor, and epidermal γδ IELs have been studied extensively (1)(2)(3)(4), the functions of intestinal γδ IELs remain poorly understood. Some studies have shown that γδ IELs contribute to progression of immune-mediated colitis (5)(6)(7); other data suggest that γδ IELs contribute to mucosal homeostasis (8,9) by secreting keratinocyte growth factor (10,11) and antimicrobial peptides (12,13), suppressing CD4 + T-cell expansion through TGF-β and IL-10 production (8,9) and promoting barrier maintenance via poorly understood mechanisms (13)(14)(15). These observations and the small number of IELs relative to intestinal epithelial cells are difficult to reconcile with the widely held belief that γδ IELs have limited motility (1,16).…”

mentioning

confidence: 99%

Dynamic migration of γδ intraepithelial lymphocytes requires occludin

Edelblum¹,

Shen²,

Weber³

et al. 2012

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

151

191

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γδ intraepithelial lymphocytes (IELs) are located beneath or between adjacent intestinal epithelial cells and are thought to contribute to homeostasis and disease pathogenesis. Using in vivo microscopy to image jejunal mucosa of GFP γδ T-cell transgenic mice, we discovered that γδ IELs migrate actively within the intraepithelial compartment and into the lamina propria. As a result, each γδ IEL contacts multiple epithelial cells. Occludin is concentrated at sites of γδ IEL/epithelial interaction, where it forms a ring surrounding the γδ IEL. In vitro analyses showed that occludin is expressed by epithelial and γδ T cells and that occludin derived from both cell types contributes to these rings and to γδ IEL migration within epithelial monolayers. In vivo TNF administration, which results in epithelial occludin endocytosis, reduces γδ IEL migration. Further in vivo analyses demonstrated that occludin KO γδ T cells are defective in both initial accumulation and migration within the intraepithelial compartment. These data challenge the paradigm that γδ IELs are stationary in the intestinal epithelium and demonstrate that γδ IELs migrate dynamically to make extensive contacts with epithelial cells. The identification of occludin as an essential factor in γδ IEL migration provides insight into the molecular regulation of γδ IEL/epithelial interactions.intestine | tight junction T he intestine is one of the few peripheral tissues to contain a large population of intraepithelial lymphocytes (IELs), with one IEL for every 5-10 epithelial cells. Although the majority of these IELs express the γδ T cell receptor, and epidermal γδ IELs have been studied extensively (1-4), the functions of intestinal γδ IELs remain poorly understood. Some studies have shown that γδ IELs contribute to progression of immune-mediated colitis (5-7); other data suggest that γδ IELs contribute to mucosal homeostasis (8, 9) by secreting keratinocyte growth factor (10, 11) and antimicrobial peptides (12, 13), suppressing CD4 + T-cell expansion through TGF-β and IL-10 production (8, 9) and promoting barrier maintenance via poorly understood mechanisms (13-15). These observations and the small number of IELs relative to intestinal epithelial cells are difficult to reconcile with the widely held belief that γδ IELs have limited motility (1, 16).Further understanding of γδ IEL function will require definition of the molecular structures that regulate interactions between intestinal epithelial and γδ T cells. On the basis of the location of epithelial/γδ IEL contact sites along epithelial lateral membranes, it is likely that epithelial proteins targeted to these domains, including apical junction complex components, are involved in these interactions. Attractive candidates include E-cadherin, which can bind CD103 (α E β 7 integrin) expressed by IELs (17), as well as tight junction proteins. For example, γδ IELs express several epithelial tight junction proteins, including occludin and zonula occludens-1 (ZO-1) (18), that may bind directly or indirectly t...

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“…More specifically, it has been shown that gd T cells readily accumulate in inflamed tissues of IBD patients [22][23][24][25], although, in murine studies, gd T cells have been shown to either potently reduce [26][27][28] or exacerbate inflammation [29][30][31][32][33]. Some studies also identify gd T cells as a source of rapidly activated T cells with Th17-like effector properties providing the first line of defense against pathogens [34][35][36].…”

mentioning

confidence: 99%

CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

2011

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Foxp31 regulatory T (T REG ) cells are critical mediators of peripheral immune tolerance, and abrogation of their function provokes a variety of autoimmune and inflammatory states including inflammatory bowel disease. In this study, we investigate the functional dynamics of T REG -cell responses in a CD4) hosts to gain insights into the mechanism and cellular targets of suppression in vivo. We show that CD4 1 T effector cell transfer into T-cell-deficient mice rapidly induces mucosal inflammation and colitis development, which is associated with prominent Th1 and Th17 responses. Interestingly, we unveil a prominent role for resident cd T cells in mucosal inflammation as they promote Th1 and particularly Th17 responses in the early phase of inflammation, thus exacerbating colitis development. We further demonstrate that CD4

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Exacerbating Role of γδ T Cells in Chronic Colitis of T-Cell Receptor α Mutant Mice

Cited by 51 publications

References 49 publications

Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Dynamic migration of γδ intraepithelial lymphocytes requires occludin

CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

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Exacerbating Role of γδ T Cells in Chronic Colitis of T-Cell Receptor α Mutant Mice

Cited by 51 publications

References 49 publications

Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts

Dynamic migration of γδ intraepithelial lymphocytes requires occludin

CD4+Foxp3+ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

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CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation