The project aims at understanding the role of paternal factors at conception on the ontogeny of the offspring immune system. Adult immune-cell compartments like mast cells and macrophages are highly heterogeneous, partly because fetal-derived and bone marrow-derived immune cells co-exist in adult tissues. Maternal, intrauterine and early-life conditions may program through epigenetic mechanisms the ontogeny and function of the offspring immune system. Equally, paternal health at conception is important for offspring development and physiology. Recently, non-germ cell factors have been implicated in the paternal programming of offspring phenotypes and – of special interest here – in the modulation of immune responses in the female tract and at the maternal-fetal interface. While important to promote maternal tolerance towards the conceptus and pregnancy health, little is known on the role of paternal factors on the ontogeny and function of offspring immune system. We have recently shown that paternal circadian disruption affects offspring metabolism and feeding behavior via glucocorticoids in the seminal fluid and glucocorticoid signaling at conception. Glucocorticoids are among the most effective endogenous immune modulators and therefore altered glucocorticoid signaling at conception might lead to aberrant offspring immune development via modulation of immune response in the maternal tract and at the maternal-fetal interface. This project will thus apply a combination of mouse genetics for fate mapping and targeting of specific immune cells (in collaboration with Dr. Gentek), with single-cell (epi)genomic analyses to study the effects of glucocorticoid signaling at conception on maternal immune response to the conceptus and offspring immune development.

• Lassi M, Tomar A, Comas-Armangué G, Vogtmann R, Dijkstra DJ, Corujo D, Gerlini R, Darr J, Scheid F, Rozman J, Aguilar-Pimentel A, Koren O, Buschbeck M, Fuchs H, Marschall S, Gailus-Durner V, Hrabe de Angelis M, Plösch T, Gellhaus A, Teperino R. (2021). Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors. Sci Adv. 2021 May 26;7(22):eabg6424. doi: 10.1126/sciadv.abg6424.
• Gentek et al. (2018). Hemogenic endothelial fate mapping reveals dual developmental origin of mast cells. Immunity 2018; doi: 10.1016/j.immuni.2018.04.025; PMID 29858009
• Mass & Gentek (2021). Fetal-Derived Immune Cells at the Roots of Lifelong Pathophysiology. Frontiers in Cell and Developmental Biology 2021; doi.org/10.3389/fcell.2021.648313