Elucidate the role of death receptor 3 (DR3) in thymic immune activation in infectious disease

Death receptors (DR) have a major impact on numerous inflammatory processes in the body. DR3 signals through the cytokine TL1A and have been shown to play a crucial role in mucosal inflammation. Recently, we have identified some unexpected immune subsets exiting the thymus extracted from neonatal mice. By stimulating lobes in thymic organ culture with the cytokines TL1A and IL-18, we consistently observe major subsets of myeloid-like cells exiting the thymic lobes along with a profound loss of developing T cells. The possible development and exit of other immune cells than T cells in the thymus in any notable amounts is a novel finding. We hypothesize that the ability to shift the primary output of the neonatal thymus from T cells to myeloid-like cells through pro-inflammatory cytokines may constitute an overlooked, yet fundamental biological function. Using cutting-edge next-generation single-cell RNA sequencing and state-of-the-art functional assays we aim at phenotyping the ectopic cells exiting the thymus and getting a better understanding of their functionalities. In collaboration with the University of Copenhagen, we aim at identifying their role and localization upon commensal colonization using adoptive transfer in germ-free mice. Finally, we will investigate their role in the defense against pathogen infection. Thus, the goal of this project is to elucidate immune mechanisms that could have a substantial impact on this fundamental area of cellular immunology.