Project Details
Projekt
Deciphering the region-specific distribution and function of dendritic cell populations along the epididymis
Subject Area
Reproductive Medicine, Urology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515636567
Within the epididymis, a balanced immune regulation is essential for sperm maturation and thus, the male fertility status. An immunotolerant environment needs to be maintained for immunogenic spermatozoa to mature, yet pro-inflammatory immune responses have to be readily established against invading pathogens that ascend through the urogenital tract. While the testis is considered an immune-privileged organ, mostly mediated by the blood-testis-barrier and resident macrophages, the cellular and molecular mechanisms that balance tolerant and immunogenic immune reactions in the epididymis still need to be defined. Our previous studies revealed that the epididymis is densely populated by resident antigen presenting cells that are strategically positioned along the epididymal duct. Accordingly, proximal regions remain mostly unresponsive to bacterial infections in mice and men, while distal regions exhibit severe and persistent tissue-damaging immune responses that detrimentally affect the male fertility status. Our observations point to a unique role for Dendritic Cells (DC), which bridge the innate and adaptive immune system and balance tolerance at steady state with initiating immune response upon infection. We further hypothesize that DC within the epididymis locally differentiate into distinct functional phenotypes and thus shape the local immune environments. Within the proposed study (Project 2 of the FOR 'INFINITE'), we will use cutting-edge techniques, i.e. scRNA-seq, CODEX and high dimensional flow cytometry, to comprehensively characterize the phenotypic and functional properties of region-specific epididymal DC and compare them to testicular DC. Using 3D imaging techniques we will reconstruct the localization of these unique DC subsets in context of the epididymal vasculature and will assess the migration and T cell activation status of these DC subsets using photoconvertible in vivo models and co-culture assays. Using a mouse model of acute bacterial epididymitis and distinct transgenic mouse models for targeted DC and monocyte depletion, we will identify the direct impact of epididymal DC to the region-specific immune responses, i.e. bacterial clearance and acceleration/ suppression of pro-inflammatory processes, at acute and chronic stages of infection. In collaboration with other projects of the consortium, the interaction of DC with other immune and non-immune cells within the healthy and inflamed epididymis will further be investigated and shed light on the complex immunological interactions during UPEC infection and associated tissue-damage. Our in-depth analysis will thus provide comprehensive insights about the phenotype, distribution and activation of epididymal DC subsets under physiological and pathological conditions and will identify cellular and molecular targets that might ameliorate detrimental region-specific immunity and help improve male fertility.
DFG Programme
Research Units
