Bystander CD8 T cell memory responses partially protect mice against lethal vaginal HSV-2 challenge

Abstract

Abstract Herpes Simplex Virus type-2 (HSV-2) infection is one of the most prevalent sexually transmitted diseases, 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 reveal 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 extended our findings to determine 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 vaccine-mediated protection. Immunization with LM- OVA-induced intermediate protection from lethal viral challenge, suggesting that bystander CD8 T cells (BA-CTL) may mediate protection despite the absence of antigen-specificity. The bystander functionality could be context-dependent, and the unregulated expansion of these cells can be damaging to the host. A potential explanation of BA-CTL regulation is via the involvement of regulatory T cells (Tregs), in the absence of Treg-mediated regulation, massive expansion of BA-CTLs can be predicted. On the contrary, we found depletion of Tregs resulted in significantly fewer BA- CTLs in the vaginal tract on days 2 and 6 post-HSV-2 challenge. Hence how these cells maintain the delicate balance of protection against pathology necessitates further investigation.