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

Background & Aims: T-cell receptor (TCR) γδ T cells are an important component of the mucosal immune system and regulate intestinal epithelial homeostasis. Interestingly, there is a significant increase in γδ T cells in the inflamed mucosa of patients with ulcerative colitis (UC). However, the role of γδ T cells in chronic colitis has not been fully identified. Methods: TCRα-deficient mice, which spontaneously develop chronic colitis with many features of human UC including an increase in γδ T-cell population, represent an excellent model to investigate the role of γδ T cells in UC-like colitis. To identify the role of γδ T cells in this colitis, we herein have generated TCRγ-deficient mice through deletion of all TCR Cγ genes (Cγ1, Cγ2, Cγ3, and Cγ4) using the Cre/loxP site-specific recombination system and subsequently crossing these mice with TCRα-deficient mice. Results: An increase in colonic γδ T cells was associated with the development of human UC as well as UC-like disease seen in TCRα-deficient mice. Interestingly, the newly established TCRα^-/- × TCRγ^-/- double mutant mice developed significantly less severe colitis as compared with TCRα-deficient mice. The suppression of colitis in TCRα^-/- × TCRγ^-/- double mutant mice was associated with a significant reduction of proinflammatory cytokine and chemokine productions and a decrease in neutrophil infiltration. Conclusions: γδ T cells are involved in the exacerbation of UC-like chronic disease. Therefore, γδ T cells may represent a promising therapeutic target for the treatment of human UC.