T cell immunity in the female genital tract

Thesis (Ph.D.)--University of Washington, 2020Many pathogens of global health significance are sexually transmitted, highlighting the importance of studying immune cells in genital barrier tissues. T cells are a critical component of the immune response to viruses, yet their role in protecting the female genital tract against viral infection is incompletely understood. Here, we combined studies of the mouse and human female genital tract to characterize T cells isolated from female genital barrier tissues. In human cervicovaginal tissue, CD8 T cells resembled effector T cells, raising the question of whether they were recently activated. By employing mouse models, we found that systemic immunization resulted in a cervicovaginal CD8 T cell compartment that was poorly maintained and underwent progressive differentiation that was not observed in spleen, lymph nodes, or small intestine lamina propria. This progressive differentiation occurred over five months, after which CD8 T cells gained an effector-like phenotype, ultimately resembling human cervicovaginal CD8 T cells. Vaginal inflammation combined with vaginal antigen exposure accelerated this differentiation process. The CD8 T cell compartment induced by systemic immunization mediated partial protection against vaginal infection with herpes simplex virus type 2 (HSV-2). This protection waned over time as the loss and differentiation of the CD8 T cell compartment progressed. Together, these results demonstrate that tissue-intrinsic factors interact with environmental cues to dictate the final longevity and phenotype of the cervicovaginal CD8 T cell compartment.Women living with HSV-2 often experience recurring genital herpes lesions. We explored the T cell compartment in human genital skin during these localized HSV-2 reactivation events. Upon HSV-2 lesion formation, we found that CD4 and CD8 T cells expanded in the infected skin site and upregulated markers of proliferation and activation. Some of the expanded T cells resembled circulating memory T cells, suggesting influx of immune cells from the blood. Cell-intrinsic and cell-extrinsic regulatory mechanisms were also upregulated in HSV-2 lesions, indicating that the immune system acted to control the virus as well as limit immunopathology. Meanwhile, T cells isolated from a nearby unaffected region distinct from the HSV-2 lesion were quiescent, instead resembling the T cell isolate from genital biopsies from HSV seronegative participants. Despite the frequency of HSV-2 reactivation in people with chronic genital herpes, we did not observe evidence of T cell exhaustion or loss of functionality. After lesion resolution, the T cell infiltrate in HSV-2 lesions returned to quiescence, again resembling the T cell compartment in contralateral and seronegative control biopsies. Given these results, we conclude that T cell responses to HSV-2 reactivation events in genital skin are highly localized, include both resident T cells and circulating memory T cells, and are rapidly constrained by regulatory T cells and intrinsic regulatory mechanisms. Taken together, our data highlight unique features of T cells in the female genital tract and their roles in vaccination and viral immunity