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Functional programming of fetal γδ T cells by maternal microbial signals

par Tafesse, Yohannes
Président du jury Pochet, Stéphanie
Promoteur Vermijlen, David
Publication Non publié, 2025-10-01

Thèse de doctorat

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Résumé :

The fetal immune system develops in a unique environment that balances immune tolerance toward the semi-allogeneic mother with the need to mount effective defences against pathogens. This tightly regulated equilibrium is increasingly recognized as a window of immune imprinting, with long-lasting consequences for postnatal immunity. γδ T cells are the first T cells generated in vertebrates, and they play key roles in infection control, tissue surveillance, and barrier integrity. Yet, the maternal microbial signals shaping the fetal γδ T cell functions in the early life period remain poorly understood. This thesis investigates two major axes of maternal-derived immune signals: microbial signals originating from the maternal microbiota and its modulation via probiotic supplementation, and fetal infection resulting from congenital transmission of pathogens. Taking these two axes together, we aimed to show their converging effects on the functional programming of perinatal γδ T cells in both murine and human systems. In the first part of this work, we explore how maternal microbial cues, particularly the normal microbiota and its modulation through probiotic supplementation, influence the function of perinatal lung γδ T cells. Using mouse models, we demonstrate that maternal administration of Lacticaseibacillus rhamnosus VES001 during pregnancy lead to significant increase in the frequencies of γδ17 in the lungs of newborns. Importantly, inter-species comparative analysis of lung γδ T cells showed the enrichment of murine lungs with γδ17 cells is mirrored in the human fetal lung as well. This evolutionary conservation of tissue-specific γδ17 polarization in early life highlights a shared developmental and functional program. In the second part of this thesis, we focused on a natural model of in utero immune activation: congenital cytomegalovirus (cCMV) infection, and its effects on the γδ T cell landscape in human fetal blood. Utilizing high-dimensional single-cell RNA and TCR sequencing, we uncovered profound cCMV-induced changes in fetal γδ T cell composition and effector polarization. We showed that cCMV lead to robust expansion and differentiation of fetal blood γδ T cells toward a type-1 effector phenotype, characterized by high expression of cytotoxic mediators and NK-like receptors. Moreover, we showed association and expansion of diverse TCR clones with effector functions. Taken together, the findings in this thesis reveal maternal microbial signals as key modulator of fetal γδ T cell functions and provides novel insights into the functional plasticity and responsiveness of fetal γδ T cells to maternal derived inputs.