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26The memory CD8 T cell compartment in human cervicovaginal tissue (CVT) is phenotypically 27 and functionally distinct compared to other non-lymphoid tissues. To determine if these 28 distinctive features are driven by residence in the tissue itself, rather than a consequence of 29 local antigenic insults, we used a mouse model to assess memory CD8 T cell differentiation in 30 the CVT. Following systemic immunization to elicit a CD8 T cell response to a herpes simplex 31 virus (HSV) epitope, HSV-specific memory CD8 T cells were stably maintained in other tissues 32 but gradually declined in the CVT over 5 months post-immunization, correlating with a delay in 33 viral control upon HSV challenge. While memory cells in the periphery and small intestine 34 maintained a fairly stable phenotype after 30 days, memory CD8 T cells in the CVT gradually 35 acquired a CD103 + , TCF-1 -, granzyme B + phenotype over the 5 month time span. Notably, a 36 sizable and phenotypically similar population of CD8 T cells was also found in human CVT. Our 37 data indicate that the CVT environment itself considerably affects memory CD8 T cell 38 maintenance and differentiation, and call for a reassessment of the prevalent model of memory 39 T cell maintenance which does not currently account for tissue-specific divergence. 40Pathogens that infect mucosal barrier surfaces represent a significant global health 43 burden, yet immune cell function within reproductive mucosal tissues remains understudied. In 44 addition, the phenotypic and functional characteristics of memory T cells in cervicovaginal tissue 45 (CVT) compared to other mucosal and lymphoid organs is poorly understood, despite the 46 potentially broad importance of this cellular population in the context of sexually-transmitted 47 infections. 48We recently reported that memory CD8 T cells in the human CVT displayed unique 49 phenotypical and functional features including the presence of a subset of CD69 -CD103 -50 inflammatory CD8 T cells (1). Importantly, the majority of memory CD8 T cells in the CVT of 51 healthy women typically expressed CD103 and CD69, which are biomarkers associated with 52 tissue-residence (2-4), suggesting that most memory CD8 T cells in the human CVT stably 53 reside there. Tissue-residence itself can affect functional and phenotypical properties of T cells 54 (5)(6)(7)(8)(9)(10)(11)(12)(13), which is thought to be a consequence of exposure to metabolites, cytokines, and other 55 factors present in the tissue environment in steady state conditions(14, 15) (16). However, it is 56 unclear if the distinctive features of memory CD8 T cells in the CVT are a consequence of 57 recurring local infections and antigenic insults or driven by residence in the tissue itself. To 58 address this question, we used a mouse model system to assess memory CD8 T cell 59 differentiation and maintenance in the CVT. Specifically, we used a systemic immunization 60 strategy to induce HSV-specific memory CD8 T cells. We then tracked these antigen-specific T 61 cells across tissu...

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Herpes Simplex Virus type-2 (HSV-2) infection is one of the most prevalent sexually transmitted infections, yet no vaccine is currently available. Detailed analysis of HSV-infected human tissue revealed tissue-resident CD8 T cells (TRM) limit the duration and severity of HSV-2 episodes. Interestingly, recent studies indicate that the sensing and alarming function of CD8 TRMs is not restricted to cognate antigen interaction, but CD8 TRM can mediate protection against antigenically unrelated pathogens, termed “bystander activation.” Here, we investigated if antigen non-specific CD8 T cells could provide some degree of protection in a bystander fashion in the context of HSV infection. To test this, we created antigen non-specific memory compartments through immunization of mice with Listeria expressing ovalbumin (OVA) (LM-OVA). Mice were then challenged with wild-type HSV-2 to assess the degree of bystander-mediated protection. Immunization with LM-OVA-delayed disease progression from lethal viral challenge, suggesting that bystander CD8 T cells may mediate protection despite the lack of antigen-specificity. Furthermore, we found early infiltration of antigen-non-specific CD8 T cells (OVA-specific) in the vaginal tract in the infection setting. Additionally, assessment of the memory CD8 compartment in human vaginal tissue upon in-vitro treatment with cytokines caused bystander activation of memory CD8 T cells. Finally, we found that in-vitro treatment of CD8 T cells with cytokines delayed disease progression and reduced viral burden upon adoptive transfer. Altogether, our findings suggest that local bystander-activation of CD8 memory T cells can participate in protection from HSV-2.

Herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen that is estimated to infect around 23 million people per year. Despite high global prevalence, there are not any approved vaccines that are therapeutic or preventative. Most vaccines that we use today rely on injecting antigens intramuscularly in order to elicit an adaptive immune response. However, given that most pathogens gain entry to the host across barrier surfaces, a focus on eliciting mucosal immunity may enhance protection; vaccine-induced local immunity at the site of first pathogen exposure may have the best chance at preventing the spread of infection beyond the pathogen portal of entry. We hypothesized that a mucosal immunization would prime memory T cells to reside in vaginal tissues and provide better protection against vaginal HSV-2 exposure than other routes of immunization. Our initial data suggests that intranasal immunization is effective in protecting mice from vaginal HSV-2 infection. Ongoing work focuses on characterizing the role of vaccine-elicited mucosal CD8+ T cells in preventing infection to provide insight into the mechanisms of protection induced by mucosal immunization for HSV-2. These findings contribute to the efforts to generate an effective vaccine to prevent HSV-2 infection and disease. Supported by the Mary Gates Research Scholarship and the Art Levinson Award through the University of Washington.