RORγt+ c-Maf+ Vγ4+ γδ T cells are generated in the adult thymus but do not reach the periphery.

T cell receptor (TCR) Vγ4-expressing γδ T cells comprise interferon γ (IFNγ)- and interleukin-17 (IL-17)-producing effector subsets, with a preference for IL-17 effector fate decisions during early ontogeny. The existence of adult-thymus-derived IL-17+ T cells (γδ17) remains controversial. Here, we use a mouse model in which T cells are generated exclusively in the adult thymus and employ single-cell chromatin state analysis to study their development. We identify adult-thymus-derived Vγ4 T cells that have all the molecular programs to become IL-17 producers. However, they have reduced IL-17 production capabilities and rarely reach the periphery. Moreover, this study provides high-resolution profiles of Vγ4 T cells in the adult thymus and lymph nodes and identifies Zeb1 as a potential γδ17 cell regulator. Together, this study provides valuable insights into the developmental traits of Vγ4 T cells during adulthood and supports the idea of age-specific signals required for thymic export and/or peripheral maturation of γδ17 cells.

Very early-life exposure to microbiota-induced TNF drives the maturation of neonatal pre-cDC1.

OBJECTIVE: Induction of immune protection against pathogens is particularly crucial during the neonatal period dominated by anti-inflammatory and tolerance immunity. The preclinical study was carried out to determine whether environmental factors such as microbiota may influence early life immunity by impacting the development and the functional maturation of precursors of type 1 conventional dendritic cells (pre-cDC1), endowed with regulatory properties. DESIGN: Pre-cDC1 phenotype and cytokine expression in the spleen of neonates from antibiotic-treated mothers were established. The role of myeloid-derived tumour necrosis factor (TNF) was tested in vitro and in vivo. RNA sequencing analysis on neonatal sorted pre-cDC1 was performed. The early life protective CD8+ T-cell response against Listeria monocytogenes was monitored. RESULTS: We observed that first exposure to microbiota promotes TNF secretion by monocytes and macrophages shortly after birth. We demonstrated that this myeloid-derived inflammatory cytokine is crucial to induce the maturation of these neonatal regulatory pre-cDC1. Myeloid TNF signalling acts on C1q and ß-catenin pathway and modifies the fatty acid metabolism in neonatal pre-cDC1. Furthermore, we showed that during neonatal L. monocytogenes infection, microbiota-associated myeloid TNF promotes the capacity of these pre-cDC1 to induce protective CD8+ T-cell responses, by modulating their ability to secrete interleukin-10 (IL-10) and IL-12p40. CONCLUSION: Our findings emphasise the role of microbiota-derived TNF to kick-start the differentiation and the functional maturation of the neonatal splenic pre-cDC1 compartment. They bring a better understanding of potential mechanisms underlying some microbiota-linked immune dysfunction in early life.