Search bioRxiv⌕ Search

Biology subjects

Domenjo-Vila, E.

Publications and source records attributed to Domenjo-Vila, E..

4 recordsLinked to original sources

Tissue-specific adaptation of human T cells is preserved during tissue inflammation

T cells play an essential role in protecting tissues against pathogens and regulating tissue homeostasis. Previous studies highlight that T cells display tissue-specific phenotypic and functional properties, suggesting that T cells adapt to their local environment. Whether inflammation disrupts tissue-specific T cell adaptation remains poorly understood. To address this open question, we examined the T cell compartment - including conventional CD4 and CD8 T cells, regulatory T cells, {gamma}{delta} T cells, and MAIT cells - from healthy and inflamed human mucosal tissues. Using high-parameter spectral flow cytometry, we examined phenotype ex vivo and the functional capacity following stimulation, utilizing conventional gating and unsupervised clustering analysis approaches. Overall, we analyzed 65 tissue samples including mild, moderate, and severely inflamed oral gingiva, healthy and inflamed lung, along with healthy and inflamed tissue from the decidual-placental interface. Across these mucosal barrier tissues, we find that tissue location plays a dominant role in shaping the composition, phenotype, and functional capacity of the T cell compartment. Importantly, these tissue-specific adaptations were largely maintained during states of tissue inflammation. This included the ability to exert tissue repair functions, which was preserved across T cell subsets, even in severely inflamed tissues.

immunology↗

Mucosal tissue NK cells tune their function between optimal anti-pathogen activity and tissue protection

Preserving barrier integrity while mounting effective immunity is essential at mucosal surfaces. In examining the immune cells that mediate both inflammation and tissue homeostasis, we uncovered a dual role for natural killer (NK) cells in barrier immunity. While NK cells are known to control viral infections, here we identify a previously unrecognized reparative function for NK cells in mucosal tissues. Using single-cell RNA sequencing and high-dimensional flow cytometry, we reveal a distinct population of human mucosal NK cells marked by tissue residency, immunoregulatory profiles, and limited cytotoxic potential at homeostasis, yet highly responsive to inflammatory cues. In a mouse model of acute HSV-2 infection, NK cells are required for limiting infection-associated tissue damage. Mucosal NK cells express the epithelial growth factor amphiregulin (Areg), and their depletion leads to increased tissue barrier damage despite preserved viral clearance, suggesting a novel role in tissue protection. Mechanistically, we demonstrate that the barrier-derived cytokines IL-18 and IL-33 induce Areg expression by both human and mouse NK cells, linking local inflammatory cues to reparative NK cell programming that is able to potentiate wound healing. Together, our findings reveal a context-dependent, dual function of mucosal NK cells in immune defense and mucosal tissue protection, expanding current models of NK cell biology.

immunology↗

A novel non-invasive method to sample immune cells in the lower female genital tract

T cells in the human female genital tract (FGT)2 are key mediators of susceptibility to and protection from infection, including HIV and other sexually transmitted infections. There is a critical need for increased understanding of the distribution and activation of T cell populations in the FGT, but current sampling methods require a healthcare provider and are expensive, limiting the ability to study these populations longitudinally. To address these challenges, we have developed a method to sample immune cells from the FGT utilizing disposable menstrual discs which are non-invasive, self-applied, and low-cost. To demonstrate reproducibility, we sampled the cervicovaginal fluid (CVF)3 of healthy, reproductive-aged individuals using menstrual discs over three sequential days. CVF was processed for cervicovaginal cells, and high parameter flow cytometry was used to characterize immune populations. We identified large numbers of live, CD45+ leukocytes, as well as distinct populations of T cells and B cells. Within the T cell compartment, activation and suppression status of T cell subsets were consistent with previous studies of the FGT utilizing current approaches, including identification of both tissue resident and migratory populations. In addition, the T cell population structure was highly conserved across days within individuals but divergent across individuals. Our approach to sample immune cells in the FGT with menstrual discs will decrease barriers to participation and empower longitudinal sampling in future research studies.

immunology↗

Senescent, dysfunctional human cardiac progenitor cells (CPCs) accumulate in the aged heart and elimination of senescent cells enhances CPC activation and cardiomyocyte proliferation in aged mice

Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease (n=119), aged 32-86 years. In aged subjects (>74 years old) over half of CPCs are senescent (p16INK4A, SA-{beta}-gal, DNA damage {gamma}H2AX, telomere length, Senescence-Associated Secretory Phenotype (SASP)), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q senolytics) in vivo activates resident CPCs (0.23{+/-}0.06% vs. 0.01{+/-}0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25{+/-}0.07% vs. 0.03{+/-}0.03% vehicle; p<0.05). Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

physiology↗