An innate-like role of memory T cells in HSV-2 immunity

Abstract

Mucosal infections pose a significant global health burden and remain a top cause of mortality worldwide. Herpes Simplex Virus type-2 (HSV-2) infection is one of the most prevalent sexually transmitted infections, yet no vaccine is currently available. An understanding of the cellular composition of tissue-resident immune cells at the primary site of infection is essential for effective vaccine design for targeted immune response. Antigen-specific tissue-resident memory T cells or TRMs are critical to maintaining barrier immunity. TRMs are non-circulating memory CD8 T cells which remain poised at the barrier sites and possess an increased cytotoxic potential to antigen-reencounter, can proliferate in-situ. We previously observed that systemic immunization with an HSV glycoprotein B (gB) epitope activates mucosal CD8 TRM and confers partial protection against HSV-2 challenge. However, 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.” 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 TCR engagement. Whether "bystander T cell activation" is also an important defense mechanism in the mucosa is poorly understood. In chapter 2, we investigated if innate-like memory CD8 T cells could protect against a model mucosal virus infection, genital HSV-2. We found that immunization with an irrelevant antigen delayed disease progression from a 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-non-specific CD8 T cells, which became bystander-activated upon entering the vaginal mucosa from circulation. Further, 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. Finally, we show that bystander-activated CD8 T cells are sufficient to delay disease progression and reduce viral burden after HSV-2 infection. Altogether, our findings suggest that local bystander activation of infiltrating CD8 memory T cells contributes a fast and effective innate-like response in mucosal tissue. Consistent antigen exposure in a systemic chronic infection such as LCMV leads to T cell exhaustion; however, whether episodic mucosal localized infection results in T cell exhaustion has not been well studied. Detailed analysis of HSV-infected human tissue reveals that TRMs limit the duration and severity of HSV-2 shedding episodes. Since CD8 TRMs are subjected to recurrent antigen exposure due to the episodic nature of HSV-2 infection, it is important to assess the cellular kinetics and functionality of the HSV-specific and non-specific population within the genital mucosa upon episodic infection. We investigated the T cell phenotype and function within HSV-2 lesion in HSV-2 positive patients and within the genital mucosa in HSV infected mice at the acute phase, effector phase and the lesion resolution phase in chapter 3. Our findings indicate that T cells maintain their functionality in response to recurrent antigen exposure rather than becoming functionally exhausted.