NF-κB/OCT-1 Mediated Upregulation of CXCL14 Chemokine Mobilizes Mucosal Effector Memory CD44+CD62L-CD4+ and CD8+ TEM Cells, and NK Cells Associated with Protection Against Genital Herpes

Background: Mucosal chemokines (eg, CCL25, CCL28, CXCL14, and CXCL17) play key roles in protecting mucosal surfaces against invading infectious pathogens. However, their specific contributions to protection against genital herpes remain to be fully elucidated. Here, we investigated the role of CXCL14 as a mediator of mucosal immunity against genital HSV-2 infection and disease. Methods: CXCL14 expression was analyzed in HSV-specific CD8+ T cells from HSV-2–infected asymptomatic and symptomatic women, in primary human vaginal epithelial cells, and in a murine genital HSV-2 infection model. CXCL14(–/–) deficient mice and wild-type (WT) mice were compared for genital disease severity, vaginal viral loads, survival, immune cell recruitment, and T-cell effector function following intravaginal HSV-2 infection. Chromatin immunoprecipitation assays were performed to identify transcription factors binding to the CXCL14 promoter after HSV-2 infection. Results: CXCL14 was homeostatically expressed at the genital tract mucosal surface, and HSV-specific CD8+ T cells from HSV-2–infected asymptomatic women expressed significantly higher levels of CXCL14 than those from symptomatic women. HSV-2 infection rapidly induced CXCL14 transcription and production in primary human vaginal epithelial cells and in murine vaginal mucocutaneous tissue. CXCL14(–/–) mice developed more severe genital lesions, higher vaginal viral loads, and lower survival compared to WT mice. In addition, CXCL14 deficiency impaired the recruitment of natural killer (NK) cells, neutrophils, and CD44+CD62L– effector memory CD4+ and CD8+ T cells to the infected vaginal mucosa. It reduced T cell effector functions, including production of IFN-γ, TNF-α, and Granzyme B. Mechanistically, NF-κB and OCT-1 transcription factors bound to the CXCL14 promoter within hours of HSV-2 infection. Conclusions: Our findings demonstrate that NF-κB- and OCT-1–driven CXCL14 expression is crucial for orchestrating early innate and T-cell responses that protect against genital HSV-2 infection and disease. These results suggest that CXCL14 is an important immunoregulatory chemokine triggered early after epithelial viral infection, facilitating the induction of effective mucosal protective immunity against genital herpes.