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

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.

The Anatomical Location Shapes the Immune Infiltrate in Tumors of Same Etiology and Affects Survival

“…Furthermore, the percentages of CD8 þ Tn, Tcm, Tem, and Temra found in cervical carcinoma are comparable with previous reported findings in normal cervical tissue (14). Moreover, the numbers of cervical carcinoma resident (CD8 þ CD103 þ ) T cells display the same mean and variability as found in normal cervix (34), suggesting that these cells are already present in normal tissue and thus not appear due to malignant transformation. It seems that the different immune contextures developed in primary OPSCC and cervical carcinoma reflect the immune contexture found in the tissue of origin.…”

Resident Memory-Like Tumor-Infiltrating Lymphocytes (TILRM): Latest Players in the Immuno-Oncology Repertoire

“…Although this study does not contradict earlier findings demonstrating CD103 expression by tumor-reactive TIL, if correct, it suggests that TIL RM populations may actually be more heterogeneous than previously thought. Indeed this might be particularly relevant in the gynecologic cancer setting as HSV-2 reactive T cells with a typical T RM phenotype have been reported to be present in the cervical tissue of women with known HSV-2 infection ( 63 ) and the numbers of typical T RM in the fallopian tube are reported to increase with age ( 64 ). Perhaps these pathogen-specific TIL RM populations in previously healthy gynecologic barrier tissues simply “come along for the ride” once the tissue becomes cancerous, and perhaps even co-exist with nascent tumor-specific TIL RM populations.…”

Functional recreation of age-related CD8 T cells in young mice identifies drivers of aging- and human-specific tissue pathology

“…Shortly after puberty, an aberrant subpopulation of phenotypically and functionally distinct memory CD8 T cells begins to progressively accumulate in the circulation, partially in response to thymic involution ( Zlamy et al, 2016 ; LeMaoult et al, 2000 ; Messaoudi et al, 2006 ). This subpopulation exhibits age-related changes in homing to tissues including brain in both humans and mice, and expresses markers of resident-memory CD8 T cells (CD8 T RM ) ( Park and Kupper, 2015 ; Wakim et al, 2012 ; Smolders et al, 2013 ; Ritzel et al, 2016 ; Rodriguez-Garcia et al, 2018 ). In the circulation, age-related CD8 T RM become prominent by middle age in most individual people, and can promote immune-mediated tissue damage upon re-stimulation ( Clambey et al, 2005 , 2008 ; den Braber et al, 2012 ; Schwab et al, 1997 ).…”