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Decoding early life gamma delta T cell ontogeny and their response to bacterial infection through the lens of single-cell transcriptomics

par Sánchez Sánchez, Guillem
Président du jury Pochet, Stéphanie
Promoteur Vermijlen, David
Publication Non publié, 2023-12-08

Thèse de doctorat

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Résumé :

γδ T cells are the first T cells generated in the fetus in most of the vertebrate species studied up to date. Fetal γδ T cells are well known by their peculiar thymic development structured in distinct timely-restricted waves, but the current understanding of these events is mainly limited to mouse models. In addition, accumulating evidence indicate that γδ T cells are key players in early life immunity and physiology, but again most of this knowledge is derived from observations described in mouse. Indeed, translation of γδ T cell biology findings from mouse models towards human are complicated by the lack of conservation of the γ and δ T cell receptor (TCR) loci. In this PhD thesis, the aim was to assess the development and role of γδ T cells in early life from different developmental, pathogenic and species contexts. First, the ontogeny of human γδ T cells was explored by using coupled single cell (sc) gene expression (GEX) and sc γδ TCR sequencing (TCR-seq) on fetal and pediatric γδ thymocytes. Our combined dataset of gene expression and detailed TCR information revealed distinct and age-dependent functional thymic programming of γδ T cell immunity in human and provides a resource for further study. Then, the role of human γδ T cells was studied in children with bloodstream bacterial infection (sepsis) using TCR repertoire sequencing to investigate the dynamics of this cell population upon infection in early life. We found that fetal γδ T cells expanded in an age- and pathogen-dependent manner.Finally, the ontogeny of γδ T cells was further investigated in an unconventional animal model: the cancer-resistant naked mole rat. Annotation of the TCR loci of this species allowed us to characterize in depth the nature of their T cell subsets using TCR profiling approaches at bulk and sc levels. In this animal, γδ T cell compartment is dominated by an NK-like subset that possesses an invariant fetal-derived γδ TCR that is continuously produced across life. The insights obtained by our data provide a new framework to investigate the intrinsic anticancer biology of this species from an immunological γδ-T-based perspective.The data collected in this study significantly advances our understanding of early-life γδ T cell biology, particularly in the context of humans. Our findings suggest that previously overlooked variables can influence the responses of these cells in humans, such as the role of specific TCR sequences in their functional development and their reactivity to infections. Moreover, our research in the naked-mole rat further reinforces the idea that the γδ T cell lineage and its protective roles have been strikingly conserved across evolution.Collectively these findings in humans and unconventional animal models invite further exploration into the diverse behaviors exhibited by γδ T cells, a peculiar cell type that has, likely, been accompanying animals since the dawn of vertebrate immune system.