Evidence for the opposing roles of different γδ T cell subsets in macrophage homeostasis

To ensure invading pathogens are eliminated with minimal damage to host tissues it is essential that macrophage activation be tightly regulated. Previously we demonstrated that a subset of gamma delta T cells (V gamma 1(+)) contributes to resolving pathogen-induced immune responses by killing activated macrophages. However, the exaggerated macrophage response seen in infected V gamma 1(+) T cell-deficient mice suggests that gamma delta T cells play a broader role in macrophage homeostasis and other subsets might promote macrophage activation. Using a maaophage: gamma delta Tcell co-culture system we have shown that gamma delta Tcells increase the activity of macrophages activated in vivo by Listeria monocytogenes infection. In a dose-dependent manner, gamma delta T cells up-regulated production of cytokines (TNF-alpha, IL-6, IL-10) and chemokines (MIP-1 alpha, MIP-1 beta) by Listeria-elicited macrophages. The ability to increase macrophage cytokine production was prominent among V gamma 4(+) gamma delta T cells. Reciprocally, V gamma 4(+) gamma delta T cells were activated by Listeria-elicited macrophages, resulting in production of the anti-inflammatory cytokine, IL-10. gamma delta T cell adoptive transfer experiments showed that V gamma 4(+) T cells protected TCR delta(-/-) mice against Listeria-induced liver injury and necrosis. These findings identify distinct and nonoverlapping roles for gamma delta T cell subsets in regulating macrophage function during pathogen-induced immune responses.