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

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Abstract
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 γδ T cells (Vγ1+) contributes to resolving pathogen‐induced immune responses by killing activated macrophages. However, the exaggerated macrophage response seen in infected Vγ1+ T cell‐deficient mice suggests that γδ T cells play a broader role in macrophage homeostasis and other subsets might promote macrophage activation. Using a macrophage:γδ T cell co‐culture system we have shown that γδ T cells increase the activity of macrophages activated in vivo by Listeria monocytogenes infection. In a dose‐dependent manner, γδ T cells up‐regulated production of cytokines (TNF‐α, IL‐6, IL‐10) and chemokines (MIP‐1α, MIP‐1β) by Listeria‐elicited macrophages. The ability to increase macrophage cytokine production was prominent among Vγ4+ γδ T cells. Reciprocally, Vγ4+ γδ T cells were activated by Listeria‐elicited macrophages, resulting in production of the anti‐inflammatory cytokine, IL‐10. γδ T cell adoptive transfer experiments showed that Vγ4+ T cells protected TCRδ–/– mice against Listeria‐induced liver injury and necrosis. These findings identify distinct and non‐overlapping roles for γδ T cell subsets in regulating macrophage function during pathogen‐induced immune responses.