Abstract
The ectocervix is part of the lower female reproductive tract (FRT), which is susceptible to sexually transmitted infections (STIs). Comprehensive knowledge of the phenotypes and T cell receptor (TCR) repertoire of tissue-resident memory T cells (TRMs) in the human FRT is lacking. We took single-cell RNA-Seq approaches to simultaneously define gene expression and TCR clonotypes of the human ectocervix. There were significantly more CD8+ than CD4+ T cells. Unsupervised clustering and trajectory analysis identified distinct populations of CD8+ T cells with IFNGhiGZMBloCD69hiCD103lo or IFNGloGZMBhiCD69medCD103hi phenotypes. Little overlap was seen between their TCR repertoires. Immunofluorescence staining showed that CD103+CD8+ TRMs were preferentially localized in the epithelium, whereas CD69+CD8+ TRMs were distributed evenly in the epithelium and stroma. Ex vivo assays indicated that up to 14% of cervical CD8+ TRM clonotypes were HSV-2 reactive in HSV-2–seropositive persons, reflecting physiologically relevant localization. Our studies identified subgroups of CD8+ TRMs in the human ectocervix that exhibited distinct expression of antiviral defense and tissue residency markers, anatomic locations, and TCR repertoires that target anatomically relevant viral antigens. Optimization of the location, number, and function of FRT TRMs is an important approach for improving host defenses to STIs.
Highlights
The lower female reproductive tract (FRT) includes the vagina and ectocervix, which are the major entry sites in females for sexually transmitted infections (STIs), including herpes simplex virus type 2 (HSV-2), HIV-1, and certain HPV species
To probe antigenic targets of these CD8+ TRM populations among HSV-2–seropositive women, we discovered that up to 14% of the clonotypes from both CD8+ TRM subsets in the cervix were shared with HSV-2–reactive CD8+ T cell clonotypes in matched blood
CD8+ T cells are the major contributors to the expression of IFN-γ, granzyme B (GZMB), and perforin (PRF1); CD4+ T cells dominate the expression of FOXP3, a lineage transcription factor for CD4+ Tregs, and CD40LG, a known molecule that regulates interactions between CD4+ T cells and many other cell types, including B cells and DCs [45] (Figure 2C and data not shown)
Summary
The lower female reproductive tract (FRT) includes the vagina and ectocervix, which are the major entry sites in females for sexually transmitted infections (STIs), including herpes simplex virus type 2 (HSV-2), HIV-1, and certain HPV species. Our studies using human genital skin biopsies from participants with recurrent HSV-2 infection have shown that CD8+ T cells at the dermal-epidermal junction (DEJ CD8) have the hallmarks of tissue-resident memory T cells (TRMs) and that these DEJ CD8 cells likely play critical roles in controlling recurrent HSV-2 infection in the genital skin area [8, 9]. Using cervical cytobrush and biopsy specimens, several studies have shown that the human cervix possesses HSV-reactive CD4+ and CD8+ T cells [10,11,12]. Studies using a mouse vaginal infection model with attenuated HSV-2 mutants have shown that both CD4+ and CD8+ T cells are necessary to control HSV-2 infection [13, 14]. There is a major knowledge gap in understanding T cell responses at steady-state levels in human cervix mucosa
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