IL-15 plays a critical role in the development and maturation of gammadelta intraepithelial T lymphocytes (IEL), which are known to play important roles in wound healing and resolving inflammation in mice. In this study, we found that IL-15 transgenic (Tg) mice, under the control of a MHC Class I promoter, exhibited accelerated wound healing but were highly susceptible to genital infection with HSV-2. The IEL in the skin and reproductive organs of IL-15 Tg mice produced an aberrantly higher level of TGF-beta1 upon TCR triggering than in control mice. In vivo neutralization of TGF-beta ameliorated the susceptibility of IL-15 Tg mice to genital HSV-2 infection. Taken together, overexpression of IL-15 may stimulate IEL to produce TGF-beta1, promoting wound healing but impeding protection against genital HSV-2 infection.