Protection against colitis by CD100-dependent modulation of intraepithelial γδ T lymphocyte function

Intraepithelial gamma delta T lymphocytes (gamma delta IEL) have important roles in repair of tissue damage at epithelial sites, such as skin and intestine. Molecules that orchestrate these gamma delta T-cell functions are not well defined. Recently, interaction of the semaphorin CD100 on skin gamma delta Tcells with plexin B2 on keratinocytes was shown to be important for effective gamma delta T-cell function in he epidermis, which raised the possibility that CD100 may exert similar functions in the intestinal tract. In this study, we find that CD100 is expressed on all IEL, and plexin B2 is present on all epithelial cells of the mouse colon. Using the dextran sulfate sodium (DSS) mouse model of colitis, disease severity is significantly exacerbated in CD100-deficient (CD100 (1) ) mice, with increased colon ulceration and mucosal infiltration with inflammatory cells. The severe colitis in CD100(-1-) mice is attributable to the failure of the colon epithelium to mount a proliferative response to damage. Unlike wild-type gamma delta IEL, gamma delta IEL from CD100(-1-) mice fail to produce keratinocyte growth factor-1 (KGF-1) in response to DSS treatment. Administration of recombinant KGF-1 to CD100(-1-) animals ameliorates disease and reverses colitis susceptibility. These results demonstrate that CD100-mediated signals are critical for effective activation of gamma delta IEL to produce growth factors, including KGF-1, that are required for healing of the colon epithelium during colitis.