Project 1 - Local regulation of T cell differentiation and function in the reproductive mucosa

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PROJECT SUMMARY CD8 T cells defend against tumors and intracellular pathogens. The classical immunosurveillance paradigm assumes that most CD8 T cells survey for infections by constantly circulating through blood, tissues, and lymph. This view is being significantly revised after the recent discovery that a large fraction of memory CD8 T cells in barrier mucosal organs do not routinely circulate. This later group of cells, named resident memory T cells (TRM), have shown to be particularly critical for controlling infections that target mucosal organs like the female reproductive tract (FRT). As a barrier tissue FRT is a frequent target of number of intractable pathogens including HIV and Herpes Simplex virus. There is a growing consensus that vaccines against these diseases should strive to generate both antibody as well as T-cell mediated responses. And as such efforts to increase antiviral T cell density in reproductive mucosae has been a key driving factor in the field of T cell vaccinology. Success in these attempts will depend on a complete understanding of mucosal TRM biology. We hypothesize that maintaining abundant functional TRM in the mucosae is predicated on TRM’s successful adaptation to the local mucosal environment; a process that is poorly understood. Local tissue-derived factors are thought to be critical regulators of this process and represent important targets that can be modulated to influence the quantity, quality and distribution of TRM. We plan to explore two key aspects of mucosal adaptation program of FRT CD8 TRM. Under the first aim, we will perform transcriptional and epigenetic analysis of T cells at distinct stages as it enters the FRT and differentiate into mature TRM cells. Our phenotypic characterization has revealed a significant heterogeneity among the TRM populations and the transcriptional and chromatin landscape analysis at single cell resolution will allow us to gain deeper insights into the differentiation trajectories of these populations and molecular regulators that control this process. Under the second aim, we will interrogate molecules that have been implicated in antiviral CD8 TRM establishment, differentiation and function. Our pilot data indicates involvement of local sex steroids and transforming growth factor-beta (TGF-b) in FRT TRM differentiation and function. Understanding the molecular underpinnings of how FRT CD8 TRM differentiation and function are regulated will reveal critical targets that can be exploited to both improve CD8 T cell quantity and quality in the reproductive mucosa for vaccination.