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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+ 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+ 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+ 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+ T cells, which became bystander-activated only within the infected mucosal tissue. Critically, we show that bystander-activated CD8+ 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+ T cells from mice and humans. Altogether, our findings suggest that local bystander activation of CD8+ 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+ T cells (CD8+ TRMs) have been shown to be critically important in this process. CD8+ TRMs are localized at tissue sites of prior viral replication and have been demonstrated to trigger an antiviral state within the tissue microenvironment (1, 2). CD8+ TRMs mediate rapid target cell killing, and further, T cell receptor-mediated (TCR-mediated) activation of CD8+ TRMs can protect against unrelated pathogens in an IFN-y-dependent manner in the female genital tract (FGT) and skin, referred to as a sensing and alarm function of CD8+ TRMs (1, 2). Thus, these studies showed that TCR-mediated TRM reactivation initiates a broad antiviral state not limited to the primary pathogen. However, it is unclear whether this state can be elicited in the absence of cognate antigen. This is an important question to address, because a TCR dependency would indicate that the TRM alarm...