gamma-glutamyltranspeptidase knockout mice as a model for understanding the consequences of diminished glutathione on T cell-dependent immune responses

gamma-Glutamyltranspeptidase (GGT) catalyzes the first step in the extracel lular hydrolysis of glutathione (GSH) and plays a critical role in GSH recy cling; however, little is known about the impact of diminished GGT activity on immune function. We report here that GGT knockout (GGT(-/-)) mice have a 30 % decrease in splenic GSH and a 50 % reduction in thymus and spleen ce llularity. The decreased cellularity was not selective for one population o f cells, as each population was equivalently reduced. Following antigen cha llenge, GSH levels were reduced by 20-40 % in CD4(+) and CD8(+) T cells fro m GGT(-/-) mice when compared to T cells from wild-type mice. To test wheth er decreased GSH impairs immunity, we examined immune responsiveness follow ing in vivo challange with four different T cell-dependent stimuli. While t here was no alteration in the antibody response to ovalbumin and sheep eryt hrocytes, cytotoxic T lymphocyte and alloantibody activity against P815 cel ls were decreased by 30 % and 65 %, respectively. Compared to wild-type lit termates, anti-CD3-induced IL-2 and IL-6 production were also diminished in GGT(-/-) mice. These results demonstrate differential effects of decreased GSH on in vivo immune responsiveness to distinct stimuli, and suggest an i mportant immunoregulatory role for GSH.