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

Marta Rodriguez‐Garcia,Fiona D Barr,Charles R Wira,Jared M Fortier

doi:10.1111/acel.12733

Abstract

SummaryAs women age, susceptibility to systemic and genital infections increases. Tissue‐resident memory T cells (TRMs) are CD103+ CD8+ long‐lived lymphocytes that provide critical mucosal immune protection. Mucosal dendritic cells (DCs) are known to induce CD103 expression on CD8+ T cells. While CD103+ CD8+ T cells are found throughout the female reproductive tract (FRT), the extent to which aging impacts their presence and induction by DCs remains unknown. Using hysterectomy tissues, we found that endometrial CD103+ CD8+ T cells were increased in postmenopausal compared to premenopausal women. Endometrial DCs from postmenopausal women were significantly more effective at inducing CD103 expression on allogeneic naïve CD8+ T cells than DCs from premenopausal women; CD103 upregulation was mediated through membrane‐bound TGFβ signaling. In contrast, cervical CD103+ T cells and DC numbers declined in postmenopausal women with age. Decreases in DCs correlated with decreased CD103+ T cells in endocervix, but not ectocervix. Our findings demonstrate a previously unrecognized compartmentalization of TRMs in the FRT of postmenopausal women, with loss of TRMs and DCs in the cervix with aging, and increased TRMs and DC induction capacity in the endometrium. These findings are relevant to understanding immune protection in the FRT and to the design of vaccines for women of all ages.

Highlights

Epidemiological studies show a global increase in the incidence of sexually transmitted infections (STIs), including new HIV infections, in older adults (CDC, 2016; Ghosh, Rodriguez-Garcia & Wira, 2013)
We recently described a compartmentalized distribution of dendritic cells (DCs) in the female reproductive tract (FRT), with specific DC subsets restricted to the EM, while other subsets were distributed throughout the upper and lower FRT (Rodriguez-Garcia et al, 2017)
The decrease in CD103+ T cells after proliferation in the presence of SB431542 was not a consequence of reduced proliferation, as demonstrated by the lack of changes in percentage of proliferating T cells (Figure 3d). These results demonstrate a selective regulation by DCs of the induction of CD103 expression on CD8+ T cells through the TGFb signaling pathway

Summary

| INTRODUCTION

Epidemiological studies show a global increase in the incidence of sexually transmitted infections (STIs), including new HIV infections, in older adults (CDC, 2016; Ghosh, Rodriguez-Garcia & Wira, 2013). Studies with human DCs from the lung and vaginal mucosa demonstrate that certain DC subsets can induce CD103+ T cells with tissue-resident characteristics (Duluc et al, 2013; Yu et al, 2013), suggesting that tissue DCs have the ability to control mucosal accumulation of TRMs. While it is known that TRMs are present in the FRT, the extent to which aging influences their distribution and regulation in different anatomical locations within the FRT is unknown. While it is known that TRMs are present in the FRT, the extent to which aging influences their distribution and regulation in different anatomical locations within the FRT is unknown It is unknown whether DCs from FRT sites other than the vagina have the ability to induce TRMs, and how aging and menopause impact their function. Our findings have broad implications, since they are relevant for explaining the increased risk of infection (STIs) in older women, immunological control of gynecological cancers, and to more fully understand the immunology of pregnancy

| RESULTS

C TGFβ blockade blockade blockade

Findings

| DISCUSSION

| EXPERIMENTAL PROCEDURES