Mucosal CCL28 Chemokine Improves Protection against Genital Herpes through Mobilization of Antiviral Effector Memory CCR10+CD44+ CD62L-CD8+ T Cells and Memory CCR10+B220+CD27+ B Cells into the Infected Vaginal Mucosa
Four major mucosal-associated chemokines, CCL25, CCL28, CXCL14, and CXCL17, play an important role in protecting mucosal surfaces from infectious pathogens. However, their role in protection against genital herpes remains to be fully explored. The CCL28 is a chemoattractant for the CCR10 receptor-expressing immune cells and is produced homeostatically in the human vaginal mucosa (VM). In this study, we investigated the role of the CCL28/CCR10 chemokine axis in mobilizing protective antiviral B and T cell subsets into the VM site of herpes infection. We report a significant increase in the frequencies of HSV-specific memory CCR10+CD44+CD8+ T cells, expressing high levels of CCR10, in herpes-infected asymptomatic (ASYMP) women compared with symptomatic women. Similarly, a significant increase in the CCL28 chemokine (a ligand of CCR10), was detected in the VM of herpes-infected ASYMP C57BL/6 mice, associated with the mobilization of high frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and memory CCR10+B220+CD27+ B cells in the VM of HSV-infected ASYMP mice. Inversely, compared with wild-type C57BL/6 mice, the CCL28 knockout (CCL28-/-) mice (1) appeared to be more susceptible to intravaginal infection and reinfection with HSV type 2, and (2) exhibited a significant decrease in the frequencies of HSV-specific effector memory CCR10+CD44+CD62L-CD8+ TEM cells and of memory CD27+B220+ B cells in the infected VM. These findings suggest a critical role of the CCL28/CCR10 chemokine axis in the mobilization of antiviral memory B and T cells within the VM to protect against genital herpes infection and disease. Overall design: This study is supposed to investigate the functions and mechanisms asociated with mucosal chemokines in protecting mucosal surfaces from infectious pathogens. Their role in context to genital herpes is yet to be explored fully. This study investigated the role of CCL28/CCR10 chemokine axis in mobilizing protective antiviral B and T cell subsets into the VM site of herpes infection. In this study, we evaluated the potential use of the mucosal chemokine CCL28 to improve genital herpes immunity and protect against infection and disease caused by HSV and potentially other sexually transmitted viruses. We have studied the (i) genital infection of mice with HSV-2 by viral titration, (ii) monitored the genital herpes infection and disease scoring in mice, (iii) Bulk RNA sequencing on sorted CD81 T cells, (iv) Differential gene expression, (v) function of different immune cell markers by FACS, (vi) HSV-2 specific Ab secreting cell ELISPOT assay, (vii) immunohistochemistry for human VM tissue to see the immune cell infiltrations into the VM tissue sections. We performed gene expression profiling analysis using RNA-Seq on 8 human samples. All samples were female herpes subjects categorised into Asymptomatic (n = 4), and Symptomatic (n = 4).