Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract

Abstract

Local mucosal cellular immunity is critical in providing protection from HSV-2. To characterize and quantitate HSV-2-reactive mucosal T cells, lymphocytes were isolated from endocervical cytobrush and biopsy specimens from 17 HSV-2-infected women and examined ex vivo for the expression of markers associated with maturation and tissue residency and for functional T cell responses to HSV-2. Compared to their circulating counterparts, cervix-derived CD4+ and CD8+ T cells were predominantly effector memory T cells (CCR7−/CD45RA−) and the majority expressed CD69, a marker of tissue residency. Co-expression of CD103, another marker of tissue residency, was highest on cervix-derived CD8+ T cells. Functional HSV-2 reactive CD4+ and CD8+ T cells responses were detected in cervical samples and a median of 17% co-expressed CD103. HSV-2 reactive CD4+ T cells co-expressed IL-2 and were significantly enriched in the cervix compared to blood. This first direct ex vivo documentation of local enrichment of HSV-2 reactive T cells in the human female genital mucosa is consistent with the presence of antigen-specific tissue-resident memory T cells. Ex vivo analysis of these T cells may uncover tissue-specific mechanisms of local control of HSV-2 to assist the development of vaccine strategies that target protective T cells to sites of HSV-2 infection.

Aging impacts CD103+CD8+ T cell presence and induction by dendritic cells in the genital tract

“…CD69 was widely expressed on FRT T cells, while CD103 expression was more restricted. Since CD103 + T cells co‐stained for CD69 (Figure S1b), consistent with previous reports (Posavad et al., 2017), we focused our studies on the CD103 + CD3 + T cell subset. Consistent with our previous observations (Rodriguez‐Garcia et al., 2017), CD103 + T cells were present at the three sites analyzed with no significant differences between upper and lower FRT (Figure 1b).…”

“…Whether implantation failure can be triggered by alterations in the resident T‐cell populations identified in our study remains to be determined. In contrast to the EM, CD103 + T cells are abundant in the cervix from premenopausal women, consistent with higher exposure to pathogens and the need for protection from potential ascending pathogens (Posavad et al., 2017). Our findings are in agreement with our previous demonstration of increased CD8 + T cell cytotoxic activity in the cervix of premenopausal women when compared to the endometrium (White et al., 1997) and with mouse models demonstrating that cytotoxic T cells and DC function are regulated to prevent rejection during pregnancy (Erlebacher, 2013).…”

Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory

“…One important implication is that these recall responses would remain undetected if analysis were limited to blood. The clinical relevance of local self-amplifying T cell responses may extend beyond infectious disease 40,41 , perhaps to include T-cell-driven autoimmune and allergic responses 7,42 .…”

Herpes simplex virus‐2 dynamics as a probe to measure the extremely rapid and spatially localized tissue‐resident T‐cell response

“…Patients with severe T‐cell immunodeficiency including those with AIDS or who have received immunosuppression for stem cell transplantation or solid organ transplantation are at risk of severe, persistent localized genital disease, development of drug resistance and systemic spread . The critical aspects of the cellular immune response are measured in genital mucosal tissue and sites of latency (dorsal root ganglia) rather than blood . While generation of neutralizing antibodies is believed to be a critical component of any prophylactic vaccine, humoral immune deficiency does not correlate with more severe disease.…”

“…Because genital lesions and healing tissue can be safely and repeatedly biopsied, HSV‐2 has proven to be an ideal platform for assessing the potential role of specific immunological factors in dictating episode heterogeneity. Detailed, serial analysis of infected human tissue has revealed a role for tissue resident CD8+ T cells (T RM ) in limiting the duration of HSV‐2 episodes . T RM are a subset of T‐cells which remain lodged within solid tissues without recirculating in blood and provide in situ immunosurveillance at prior sites of infection .…”