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Mucosal infections pose a significant global health burden. Antigen-specific tissue-resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory [CD8.sup.+] T cells may also provide innate-like protection against antigenically unrelated pathogens independent of T cell receptor engagement. Whether bystander T cell activation is also an important defense mechanism in the mucosa is poorly understood. Here, we investigated whether innate-like memory [CD8.sup.+] T cells could protect against a model mucosal virus infection, herpes simplex virus 2 (HSV-2). We found that immunization with an irrelevant antigen delayed disease progression from lethal HSV-2 challenge, suggesting that memory [CD8.sup.+] T cells may mediate protection despite the lack of antigen specificity. Upon HSV-2 infection, we observed an early infiltration, rather than substantial local proliferation, of antigen- nonspecific [CD8.sup.+] T cells, which became bystander-activated only within the infected mucosal tissue. Critically, we show that Bystander-activated [CD8.sup.+] T cells are sufficient to reduce early viral burden after HSV-2 infection. Finally, local cytokine cues within the tissue microenvironment after infection were sufficient for bystander activation of mucosal tissue memory [CD8.sup.+] T cells from mice and humans. Altogether, our findings suggest that local bystander activation of [CD8.sup.+] memory T cells contributes a fast and effective innate-like response to infection in mucosal tissue., Introduction Maintaining a balance of protection from pathogens while minimizing pathology is a perpetual process in mucosal barrier tissues, and tissue-resident memory [CD8.sup.+] T cells ([CD8.sup.+] TRMs) have been shown [...]

Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent in reproductive-age women worldwide. Adverse outcomes associated with BV include an increased risk of sexually acquired Human Immunodeficiency Virus (HIV), yet the immunological mechanisms underlying this association are not well understood. To investigate BV driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and peripheral blood mononuclear cells (PBMC). Immunofluorescence analysis of genital mucosal tissues revealed a reduced density of CD3 + CD4 + CCR5 + cells in the VT lamina propria of individuals with compared to those without BV (median 243.8 cells/mm 2 BV- vs 106.9 cells/mm 2 BV+, p=0.043). High-parameter flow cytometry of VT biopsies revealed an increased frequency in individuals with compared to those without BV of dysfunctional CD39 + conventional CD4 + T cells (Tconv) (median frequency 15% BV- vs 30% BV+, p adj =0.0331) and tissue-resident CD69 + CD103 + Tconv (median frequency 24% BV- vs 38% BV+, p adj =0.0061), previously reported to be implicated in HIV acquisition and replication. Our data suggests that BV elicits diverse and complex VT T cell alterations and expands on potential immunological mechanisms that may promote adverse outcomes including HIV susceptibility.