Changes in Human Mucosal γδ T Cell Repertoire and Function Associated with the Disease Process in Inflammatory Bowel Disease

McVay, Laila D.; Li, Baiqing; Biancaniello, Renée; Creighton, Mary Anne; Bachwich, Dale; Lichtenstein, Gary R.; Rombeau, John L.; Carding, Simon R.

doi:10.1007/bf03401672

Cited by 87 publications

(55 citation statements)

References 66 publications

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“…Indeed, it has already been reported that environmental exposures influence γδ T cell frequency in human peripheral blood (25) and that stable expansions of Vδ2 T cells can occur in the circulation of patients with IBD (45,46). Consistent with these data, Vδ2 T cells have also been identified in the gut in a small number of CD patients (13,14), although the role played by these cells in mucosal inflammation in CD has, until now, remained obscure.…”

Section: Discussionmentioning

confidence: 60%

“…These data indicate a potential role for Vδ2 T cells in the pathology of Crohn's disease (CD), which is characterized by enhanced effector function of CD4 + T cells directed against components of the gut microbiota. In addition to our own detection of Vδ2 T cells in human colonic lamina propria in situ (11), these cells have also been observed in gastrointestinal lymphoid tissues (12) and were previously identified in the gut in a small number of CD patients (13,14), but the role played by these cells in mucosal inflammation in CD is currently unknown.…”

Section: Introductionmentioning

confidence: 60%

“…To assess the effects of thiopurine treatment, some CD patients were recruited immediately prior to commencing AZA therapy, and longitudinal blood sampling was conducted over a followup period of 6 months. The analyses of Vδ2 T cell subset distribution in peripheral blood were conducted in a subgroup of pediatric CD patients (mean age, 13 years [range [7][8][9][10][11][12][13][14][15][16][17][18][19]; 50% male; CRP, mean 12.5 mg/l [range 5-39 mg/l]) and sex/age/ethnicity-matched IBS controls (mean age, 13 years [range [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]; 50% male; CRP, <5 mg/l) in order to limit the effects of demography, historical pathogen exposure, and concomitant therapies.…”

Section: Methodsmentioning

confidence: 99%

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Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

McCarthy¹,

Hedin²,

Sanders³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

McCarthy¹,

Hedin²,

Sanders³

et al. 2015

J. Clin. Invest.

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“…γδ IELs are involved in the regulation of the mucosal microenvironment in response to intestinal disease, including inflammatory bowel disease (44), celiac disease, graft-vs.-host disease (45), and parasite infection (14,15). However, the precise role of γδ IELs remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Dynamic migration of γδ intraepithelial lymphocytes requires occludin

Edelblum¹,

Shen²,

Weber³

et al. 2012

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

153

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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“…γδ T cells express Rorγt and IL-23R and are another source of IL-17 and IL-22, which can be produced both in IL-23-dependent and independent manner. In peripheral blood as well the intestines [146][147][148] of active IBD patients, elevated percentage and absolute number of γδ T cells were reported. Both tissue protective and pro-inflammatory roles in murine IBD models have been described for γδ T cells.…”

Section: γδ T Cellsmentioning

confidence: 99%

Interleukin 23 in IBD Pathogenesis

Eken¹,

Oukka²

2016

New Insights Into Inflammatory Bowel Disease

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Interleukin-23 (IL-23) is a cytokine that belongs to the IL-12 cytokine family that is produced mainly by antigen-presenting cells. IL-23 receptor is expressed by various innate and adaptive immune cells, including group 3 innate lymphoid cells (ILC3), neutrophils, γδ T cells, Th17 and natural killer T (NKT) cells. IL-23 regulates various functions of the responding cells critical for host protective responses but is also implicated in many chronic inflammatory diseases including inflammatory bowel diseases (IBD). IL-23 receptor signaling components and downstream effector cytokines IL-17A/F, interferon-gamma (IFN-γ), IL-22, granulocyte macrophage colonystimulating factor (GMCSF) have been shown to impact IBD-like disease development in various animal models; therapeutic approaches targeting the IL-23 pathway in IBD are in clinical trials. In this chapter, we attempt to review the literature on IL-23-mediated IBD pathogenesis. We did this by gathering the current information about the individual IL-23-producing and IL-23-responsive cells as to how they contribute to IBD pathology through various inflammatory mediators.

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Changes in Human Mucosal γδ T Cell Repertoire and Function Associated with the Disease Process in Inflammatory Bowel Disease

Cited by 87 publications

References 66 publications

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

Dynamic migration of γδ intraepithelial lymphocytes requires occludin

Interleukin 23 in IBD Pathogenesis

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