Exacerbating role of γδ T cells in chronic colitis of T-cell receptor a mutant mice

Background & Aim: T-cell receptor (TCR) gamma delta T cells are an important component of the mucosal immune system and regulate intestinal epithelial homeostasis. Interestingly, there is a significant increase in gamma delta T cells in the inflamed mucosa of patients with ulcerative colitis (UC). However, the role of gamma delta T cells in chronic colitis has not been fully identified. Methods: TCR alpha-deficient mice, which spontaneously develop chronic colitis with many features of human UC including an increase in gamma delta T-cell population, represent an excellent model to investigate the role of gamma delta T cells in UC-like colitis. To identify the role of gamma delta T cells in this colitis, we herein have generated TCR gamma-deficient mice through deletion of all TCR C gamma genes (C gamma 1, C gamma 2, C gamma 3, and C gamma 4) using the Cre/loxP site-specific recombination system and subsequently crossing these mice with TCR alpha-deficient mice. Results: An increase in colonic gamma delta T cells was associated with the development of human UC as well as UC-like disease seen in TCR alpha-deficient mice. Interestingly, the newly established TCR alpha(-/-) x TCR gamma(-/-) double mutant mice developed significantly less severe colitis as compared with TCR alpha-deficient mice. The suppression of colitis in TCR alpha(-/-) x TCR gamma(-/-) double mutant mice was associated with a significant reduction of proinflammatory cytokine and chemokine productions and a decrease in neutrophil infiltration. Conclusions: gamma delta T cells are involved in the exacerbation of UC-like chronic disease. Therefore, gamma delta T cells may represent a promising therapeutic target for the treatment of human UC.