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

Abstract

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.

Pivotal role of tissue-resident memory lymphocytes in the control of mucosal infections: can mucosal vaccination induce protective tissue-resident memory T and B cells?

“…Indeed, it was shown that a subset of vaginal CD8 T cells which were unspecific to the HSV antigen used for immunization, could play a partial role in genital protection. In this HSV challenge model, both peripheral CD8 T cells able to migrate to inflamed vaginal tissue and vaginal CD8 Trm of irrelevant antigen specificity were involved in this innate-like function (24).…”