Transcriptional Regulation of Innate T cell fate

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Project Summary InnateT cells are a collection of T cells withimportant regulatory functions that have a crucial role in immunity towards tumors, bacteria, viruses, and in cell-mediated autoimmunity. Due large quantities of cytokines upon activation, immune response populations glycolipid cells T commitment to innate T cells act as bridges between the innate and adaptive systems a nd ontribute greatly In mice, this swiftness of reflects their acquisition f functionality during their development in the thymus. Three major within the innate T cell group are recognized namely, the invariant NKT cells that recognize antigens presented by non-polymorphic CD1d molecules, the mucosal associated invariant T (MAIT) that recognize vitamin metabolites presented by the non-polymorphic MR1 molecules, and the certain  cells which antigen specificities remain uncertain. We have established an in vitro system t hat mimics the of double positive precursor cells to the innate T cell lineage and we propose to their ability to promptly secrete c to immune regulation and host protection. o , deconstruct the early transcriptional and epigenetic events that accompany this fate commitment (Aim 1). In this way, we will identify manipulation early factors that influence innate T cell development, providing the possibility for selective of innate T cell lineage specification. We will then investigatewhether human innate T cells acquire an innate-like transcriptional program in the thymus similarly to their mouse counterparts and whether this program is shared between the two species. To do so, we will profile the transcriptomes of iNKT and MAIT cells purified from neonatal human thymi at the single cell level. In addition, we will extend our knowledge of innate T cell lineage commitment by also studying CD1a-restricted T cells, which do not exist in mice (Aim 2). Given their capacity to link key inflammatory axes of innate and adaptive immunity, a better understanding of the molecular basis underpinning innate T cell development and plasticity, and how much this feature accounts for their pathophysiological roles, is critical for developing novel therapeutic approaches.