CXCL17 Chemokine–Dependent Mobilization of CXCR8+CD8+ Effector Memory and Tissue-Resident Memory T Cells in the Vaginal Mucosa Is Associated with Protection against Genital Herpes

Abstract

Circulating conventional memory CD8 T cells (i.e., the CD8 effector memory T [T] cell and CD8 central memory T [T] cell subsets) and the noncirculating CD8 tissue-resident memory T (T) cell subset play a critical role in mucosal immunity. Mucosal chemokines, including the recently discovered CXCL17, are also important in mucosal immunity because they are homeostatically expressed in mucosal tissues. However, whether the CXCL17 chemokine contributes to the mobilization of memory CD8 T cell subsets to access infected mucosal tissues remains to be elucidated. In this study, we report that after intravaginal HSV type 1 infection of B6 mice, we detected high expression levels of CXCL17 and increased numbers of CD44CD62LCD8 T and CD103CD8 T cells expressing CXCR8, the cognate receptor of CXCL17, in the vaginal mucosa (VM) of mice with reduced genital herpes infection and disease. In contrast to wild-type B6 mice, the CXCL17 mice developed 1) fewer CXCR8CD8 T and T cells associated with more virus replication in the VM and more latency established in dorsal root ganglia, and 2) reduced numbers and frequencies of functional CD8 T cells in the VM. These findings suggest that the CXCL17/CXCR8 chemokine pathway plays a crucial role in mucosal vaginal immunity by promoting the mobilization of functional protective CD8 T and CD8 T cells, within this site of acute and recurrent herpes infection.

Cxcl17 -/- mice develop exacerbated disease in a T cell-dependent autoimmune model

“…The presence of lymphocytic infiltrates in CNS has been well established as a clinical feature of multiple sclerosis, EAE, and many chronic inflammatory conditions . CXCL17 is known to be involved in recruiting myeloid cells to the mucosa and we have recently shown that CXCL17 −/ − plays a role in protection against genital herpes by recruiting effector memory CD8 T cells . We therefore sought to investigate whether CXCL17 plays any role in trafficking of lymphocytes to the CNS during EAE.…”

“…In support of this conclusion, Cxcl17/ −/− mice exhibit a paucity of macrophages in the lung . CXCL17 also shows the highest expression (among several mucosal chemokines) in the healthy mouse vagina and may play a role regulating the microbiome there . Another important observation from that study was that CXCL17 is important to control immune responses against herpesvirus in the vagina, which are depended on recruitment of GPR35 + CD8 + effector memory cells and this depends on the recruitment of activated CD8 + effector T cells .…”

“…[30][31][32] CXCL17 is known to be involved in recruiting myeloid cells to the mucosa and we have recently shown that CXCL17 −/− plays a role in protection against genital herpes by recruiting effector memory CD8 T cells. 21 We therefore sought to investigate whether CXCL17 plays any role in trafficking of lymphocytes to the CNS during EAE. Estimating levels in CNS at onset and peak of the EAE in WT mice revealed that Cxcl17 was readily detectable in the CNS by day 18 after MOG immunization ( Fig.…”

“…We originally reported that CXCL17 is a mucosal chemokine with antimicrobial activity that is strongly expressed in the respiratory tract and digestive system, and found that it is strongly up‐regulated in several diseases affecting mucosal tissues, including idiopathic pulmonary fibrosis and Sjögren's syndrome . Moreover, reflecting its mucosal expression elsewhere, CXCL17 is also expressed in the female reproductive tract and in the urethra …”

“…17,19,20 Moreover, reflecting its mucosal expression elsewhere, CXCL17 is also expressed in the female reproductive tract and in the urethra. 21 We have also characterized a Cxcl17 −/− mouse. This mouse exhibits a paucity of macrophages in the lung, including alveolar macrophages.…”