1 PhD project offered in the IPP summer call Molecular Biomedicine & Ageing

Scientific Background

Within the epididymis, a balanced immune regulation is essential for sperm maturation and thus, the male fertility status. This 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. A dysbalanced immune regulation, i.e. caused by acute bacterial infections, frequently results in longterm fertility impairments. While the neighbouring testis is considered an immune-privileged organ, 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. Our preliminary data indicate that epididymal DC locally differentiate into distinct functional phenotypes and thus shape the local immune environments.

PhD project: Identification of organ-specific and region-specific properties of conventional dendritic cells and their impact on the disease progression of acute bacterial epididymitis

Overall Aim: To understand the epididymis-specific properties of dendritic cells under physiological conditions and to assess changes in the course of acute bacterial epididymitis leading to a loss of the local immunotolerant environment.

Cutting-edge techniques, like scRNA-seq, CODEX and high dimensional flow cytometry, will be employed to comprehensively characterize the phenotypic and functional properties of region-specific epididymal murine DC at the steady state. Furthermore, the migratory properties and kinetics as well as the T cell activation status of specialized DC subsets will be assessed using photoconvertible transgenic mouse models and in vitro co-culture assays. 

To mimic the clinical manifestations observed in epididymitis-patients, a well-established experimental mouse model of acute bacterial epididymitis will be established together with our close collaboration partners at the Justus-Liebig-Universität Gießen. Utilizing specific transgenic mouse strains targeted DC and monocyte depletions will allow us to assess the impact of DC and monocyte-derived cells on the regionalized immune response and the development of anti-sperm immunity and autoinflammatory responses.

If you are interested in this project, please select Mayer (EPI) as your project preference in the IPP application platform.

Publications relevant to this project

Pleuger C, Ai D, Hoppe ML, Winter LT, Bohnert D, Karl D, Guenther S, Epelman S, Kantores C, Fijak M, Ravens S, Middendorff R,Mayer JU, Loveland KL, Hedger M, Bhushan S, Meinhardt A. (2022) The regional distribution of resident immune cells shapes distinct immunological environments along the murine epididymis. eLife, 11:e82193. Link

Mayer JU, Hilligan KL, Chandler JS, Eccles DA, Old SI, Domingues RG, Yang J, Webb GR, Munoz-Erazo L, Hyde EJ, Wakelin KA, Tang SC, Chappell SC, von Daake S, Brombacher F, Mackay CR, Sher A, Tussiwand R, Connor LM, Ortega DG, Jankovic D, Gros GL, Hepworth MR, Lamiable O, Ronchese F (2021) Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization. Nat. Immunol., 1 (13). Link

Bosteels C, Neyt K, Vanheerswynghels M, van Helden MJ, Sichien D, Debeuf N, De Prijck S, Bosteels V, Vandamme N, Martens L, Saeys Y, Louagie E, Lesage M, Williams DL, Tang SC, Mayer JU, Ronchese F, Scott CL, Hammad H, Guilliams M, Lambrecht BN. (2020) Inflammatory Type 2 CDCs Acquire Features of CDC1s and Macrophages to Orchestrate Immunity to Respiratory Virus Infection. Immunity, 52 (6), 1039-1056 e9. Link

Fijak M, Pilatz A, Hedger MP, Nicolas N, Bhushan S, Michel V, Tung KSK, Schuppe HC, Meinhardt A (2018) Infectious, inflammatory and “ autoimmune ” male factor infertility: how do rodent models inform clinical practice?Human Reproduction Update 24:416–441. Link

Da Silva N, Smith TB (2015) Exploring the role of mononuclear phagocytes in the epididymis. Asian Journal of Andrology 17:591–596. Link

Mendelsohn AC, Sanmarco LM, Spallanzani RG, Brown D, Quintana FJ, Breton S, Battistone MA (2020) From initial segment to cauda: a regional characterization of mouse epididymal CD11c+ mononuclear phagocytes based on immune phenotype and function. American Journal of Physiology. Cell Physiology 319:C997–C1010. Link