Estradiol (E2) is a sex hormone which has shown to be protective against sexually transmitted infections such as herpes simplex virus 2 (HSV-2). However, few studies have examined the underlying mechanisms by which this occurs. Here, we investigated the effect of E2 on the establishment of memory T cells post-intranasal immunization with HSV-2. CD4+ T cell responses first appeared in the upper respiratory tract (URT) within 3 days post-immunization, before being detected in the female reproductive tract (FRT) at 7 days. E2 treatment resulted in greater and earlier Th17 responses, which preceded augmented Th1 responses in these sites. The CD4+ T cells persisted in the URT for up to 28 days, and E2 treatment resulted in higher frequencies of memory T cells. Intranasal immunization also led to the establishment of CD4+ tissue-resident memory T cells (TRM cells) in the FRT, and E2 treatment resulted in increased Th1 and Th17 TRM cells. When the migration of circulating T cells into the FRT was blocked by FTY720, immunized E2-treated mice remained completely protected against subsequent genital HSV-2 challenge compared to non-E2 controls, confirming that TRM cells alone are adequate for protection in these mice. Finally, the enhanced vaginal Th1 TRM cells present in E2-treated mice were found to be modulated through an IL-17-mediated pathway, as E2-treated IL-17A deficient mice had impaired establishment of Th1 TRM cells. This study describes a novel role for E2 in enhancing CD4+ memory T cells and provides insight on potential strategies for generating optimal immunity during vaccination. IMPORTANCE Herpes simplex virus 2 (HSV-2) is a highly prevalent sexually transmitted infection for which there is currently no vaccine available. Interestingly, the female sex hormone estradiol has been shown to be protective against HSV-2. However, the underlying mechanisms by which this occurs remains relatively unknown. Our study demonstrates that under the influence of estradiol treatment, intranasal immunization with an attenuated strain of HSV-2 leads to enhanced establishment of anti-viral memory T cell responses in the upper respiratory tract and female reproductive tract. In these sites, estradiol treatment leads to greater Th17 memory cells, which precede enhanced Th1 memory responses. Consequently, the T cell responses mounted by tissue-resident memory cells in the female reproductive tract of estradiol-treated mice are sufficient to protect mice against vaginal HSV-2 challenge. This study offers important insights regarding the regulation of mucosal immunity by hormones and on potential strategies for generating optimal immunity during vaccination.

Smokers have nasal microbiota dysbiosis, with an increased frequency of colonizing bacterial pathogens. It is possible that cigarette smoke increases pathogen acquisition by perturbing the microbiota and decreasing colonization resistance. However, it is difficult to disentangle microbiota dysbiosis due to cigarette smoke exposure from microbiota changes caused by increased pathogen acquisition in human smokers. Using an experimental mouse model, we investigated the impact of cigarette smoke on the nasal microbiota in the absence and presence of nasal pneumococcal colonization. We observed that cigarette smoke exposure alone did not alter the nasal microbiota composition. The microbiota composition was also unchanged at 12 h following low-dose nasal pneumococcal inoculation, suggesting that the ability of the microbiota to resist initial nasal pneumococcal acquisition was not impaired in smoke-exposed mice. However, nasal microbiota dysbiosis occurred as a consequence of established high-dose nasal pneumococcal colonization at day 3 in smoke-exposed mice. Similar to clinical reports on human smokers, an enrichment of potentially pathogenic bacterial genera such as Fusobacterium, Gemella, and Neisseria was observed. Our findings suggest that cigarette smoke exposure predisposes to pneumococcal colonization independent of changes to the nasal microbiota and that microbiota dysbiosis observed in smokers may occur as a consequence of established pathogen colonization.KEYWORDS bacterial colonization, cigarette smoke, microbiota, mouse model, Streptococcus pneumoniae, upper respiratory tract T he microbiota plays an important role in food metabolism, modulates the host immune system, and offers protection from pathogen invasion, termed "colonization resistance" (1-3). Bacteria colonize the skin, as well as mucosal surfaces, including the oral cavity, gut, vagina, upper respiratory tract (URT), and lungs (4-7). Emerging evidence suggests that cigarette smoke exposure is associated with URT microbiota dysbiosis and increases the frequency of asymptomatic nasal colonization by Streptococcus pneumoniae and several other pathogens (8-11). An increased incidence of nasal pneumococcal colonization, in turn, contributes to the increased risk of invasive pneumococcal disease (IPD) observed in smokers and cigarette smoke-exposed mice (12, 13).Cigarette smoke exposure is an environmental stress that may perturb the balanced

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