Development and function of innate-like gamma delta T cells

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Project Summary: Innate-like γδ T cells are unusual T cells that are highly enriched in mucosal tissues like the lung, gut, and skin, where they play critical roles in the host immune response to pathogens, in autoimmunity, in anti- tumor immunity, and in tissue repair/homeostasis. A defining characteristic of innate-like γδ T cells is their ability to rapidly produce large amounts of cytokines (e.g., IFN-γ, IL-4, and IL-17), chemokines, and growth factors which allows them to shape both the magnitude and quality of both the developing immune response. Although a large fraction of γδ T cells exhibit innate-like T cell characteristics, evidence in both mouse and humans indicates the presence of naïve, unpolarized γδ T cells. The mechanisms/pathways that confer an innate-like phenotype on developing γδ T cells remain largely undefined. Both our recently published and preliminary data indicate that the SLAM/SAP signaling pathway is intimately involved in the development and function of innate- like γδT cells, and that it works through multiple distinct pathways. Here, w e p r o p o s e t o use a single-cell multiomics approach that includes scCITEseq coupled with a customized γδ V(D)J profiling platform and scATACseq to define the gene regulatory programs that distinguish SAP-dependent innate-like γδ T cells during development. Our preliminary data suggest that the SLAM/SAP signaling pathway functions at a very early stage of γδ T cell development, is involved in shaping the γδ TCR repertoire, and reveals the presence of SAP- dependent γδ TCR clonotypes. Altogether, these published and unpublished lead us to hypothesize that SLAM/SAP signaling regulates the development of functionally distinct innate-like γδ TCR clonotypes. To test this hypothesis, we will i) define the gene regulatory programs that distinguish SAP-dependent and SAP- independent thymic γδ T cells during development and ii) define the mechanisms through which SLAM/SAP signaling regulates innate-like γδ T cell developmental and function. Upon completion of these Aims, we expect to have defined new SAP-dependent innate-like γδ T cell subsets and to have generated a comprehensive map of the SAP-dependent gene regulatory programs of γδ T cells at different stages of development. In addition, we will have made a significant step forward in defining one of the mechanisms that regulates innate-like γδ T cell development and function. We believe this information will be a critical step forward in defining the developmental requirements that define these lineages as well as their specific contributions to the immune response.