Distinct memory γδ T cell subsets are fine-tuned by TCR engagement and soluble signals to shape IFNγ and IL-17A responses

Abstract

Abstract Unconventional T cells are essential for tissue homeostasis and protection against invading pathogens at barrier sites. γδ T cells are enriched at these interfaces where they can form memory populations that can be either beneficial or detrimental depending on the functional response elicited. However, our understanding of the factors regulating memory γδ T cell generation, activation and function remains limited. Foodborne Listeria monocytogenes (Lm) infection of Batf3−/− mice revealed a critical role for Batf3-dependent dendritic cells in the generation and function of adaptive γδ T cells. In line with this observation, IFNγ and IL-17A production and IFNγ/IL-17A co-production by memory γδ T cells were induced by heat-killed Lm after 24 hours in culture, and these responses were inhibited after MHC-II or CD11c depletion. The induction of cytokine production was tightly associated with Zap70/Syk phosphorylation, indicative of TCR activation. Although IL-12 is usually associated with type 1 responses, neutralization of IL-12/23p40 dramatically impaired IL-17A production whereas IFNγ response was only marginally affected. Surprisingly, classical TH17 polarizing cytokines had little impact on IL-17A production. Despite this conventional-like response, memory γδ T cells remained able to quickly produce IL-17A in response to supernatant or live Lm independently of TCR signaling. Thus, adaptive γδ T cells are a functionally diverse population that encompasses innate- and adaptive-like responses that are fine-tuned by the γδTCR and soluble signals. These insights may facilitate the development of new strategies eliciting specific functional subsets of memory γδ T cells tailored to various intestinal disease settings.