Sexually transmitted infections (STIs) remain a hidden epidemic of significant health and economic consequence in the United States and the world. Available therapies against many STIs, including HIV and HSV, do not provide a long-term cure, have significant side effects and can be cost-prohibitive. In spite of the progress in our understanding of the viral pathogenesis and immunologic mechanisms of protection with these STIs, the method of generating protective immunity through vaccination continues to be elusive. Current research on HIV vaccination is largely focused on antibody-based approaches and while CD8 T lymphocytes have a proven protective antiviral role against HIV, this has not been translated to a successful outcome in vaccine trials. Lack of an in depth understanding of the T cell biology within frontline mucosal tissues where viral replication is occurring (e.g. female reproductive tract, FRT) is a significant barrier to unlocking the full antiviral potential of T cells. Our previous studies in rodent models suggest resident memory CD8 T cells (TRM) located in the FRT are capable of eliciting rapid antiviral responses when triggered. Hence, establishing an abundant number of highly functional CD8 TRM in the FRT to mediate rapid pathogen clearance is a key long-term goal of anti-HIV vaccination programs. However, achieving sufficient quantity and quality of mucosal TRM hinges on a detailed understanding of the different types of TRM that exist in the FRT, their differentiation paths and their functional immune contribution. Our preliminary data indicate that the CD8 TRM population in the FRT is phenotypically and functionally heterogeneous. The overall objective of this pilot proposal is to use next-generation sequencing technologies to identify distinct sub-populations of TRM that are genetically and functionally distinct. Understanding this unexplored transcriptional heterogeneity is a key first step in dissecting FRT TRM differentiation that will guide efforts to generate and maintain the optimal subpopulation of TRM in the FRT needed for effective immunosurveillance.
Memory CD8 T cells are critical for protection against intracellular pathogens and tumors. Generating a robust population of memory T cells in barrier mucosal organs where they can rapidly intercept invading pathogens is a key goal of most T-cell based vaccines. This proposal will answer fundamental gaps in our current understanding of the different memory CD8 T cells present in the genital mucosa. Findings from this study will greatly improve vaccine design against pathogens that target reproductive mucosae.