The mucosal surface of female reproductive tract (FRT) is a common site of pathogen replication. Many of these pathogens establish sexually transmitted infections (STls) that are a hidden epidemic of significant health and economic concern worldwide. Many STls, including HIV and Herpes simplex virus (HSV), lack curative therapies and would immensely benefit from preventive vaccination. Anti-HIV and HSV-2 vaccine trials that are solely focused on generating neutralizing antibodies have so far failed to provide significant protective benefits. There is a growing realization that an effective mucosal vaccine regimen should elicit both antibodies and T cells. Resident memory T cells (TRM), the dominant T cell population in the genital mucosa, represent a primary defense mechanism against intracellular pathogens. Contrary to circulating memory T cells, TRM establish permanent residence in their tissue of origin and do not routinely circulate via blood and lymph. Reductionist experiments in rodent and non-human primate models suggest a strong protective role of mucosal TRM located near the site of infection. 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 many vaccination programs. However, achieving sufficient quantity and quality of mucosal TRM hinges on a detailed understanding of the differentiation and maintenance requirement of these cells. It has been recently recognized that the local environmental milieu is a significant contributor to TRM differentiation program and their long-term maintenance. Our preliminary data indicate a critical role of estrogen in impacting FRT TRM formation. The overall objective of this proposal is to interrogate the contributions of sex-hormone and the local microbiome in shaping the FRT TRM compartment.
Under first aim, we will utilize reductionist mouse model based approaches to investigate the role CD8 T cell intrinsic estrogen signaling in establishment of FRT TRM. In the second aim, we will use germfree mice and microbiome depletion approaches to examine the influence of local microbiome on TRM formation and function. Identification of local factors that contribute to TRM differentiation and function will aid in developing methods to generate a robust T cell response in the reproductive mucosa.
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