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How the microbiota modulate immune functions remains poorly understood. Mucosal-associated invariant T (MAIT) cells are implicated in mucosal homeostasis and absent in germ-free mice. Here, we show that commensal bacteria govern murine MAIT intrathymic development, as MAIT cells did not recirculate to the thymus. MAIT development required RibD expression in bacteria, indicating that production of the MAIT antigen 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) was necessary. 5-OP-RU rapidly traveled from mucosal surfaces to the thymus, where it was captured by the major histocompatibility complex class Ib molecule MR1. This led to increased numbers of the earliest MAIT precursors and the expansion of more mature receptor-related, orphan receptor γt-positive MAIT cells. Thus, a microbiota-derived metabolite controls the development of mucosally targeted T cells in a process blurring the distinction between exogenous antigens and self-antigens.

Aims: Deciphering the innate mechanisms governing the blockade of proliferation in adult cardiomyocytes (CMs) is challenging for mammalian heart regeneration. Despite the exit of CMs from the cell cycle during the postnatal maturation period coincides with their morphological switch to a typical adult rod-shape, whether these two processes are connected is unknown. Here, we examined the role of ephrin-B1, a CM rod-shape stabilizer, in adult CM proliferation and cardiac regeneration. Methods and results: Transgenic- or AAV9-based ephrin-B1 repression in adult mouse heart led to substantial proliferation of resident CMs and tissue regeneration to compensate for apex resection, myocardial infarction (MI) and senescence. Interestingly, in the resting state, CMs lacking ephrin-B1 did not constitutively proliferate, indicative of no major cardiac defects. However, they exhibited proliferation-competent signature, as indicated by higher mononucleated state and a dramatic decrease of miR-195 mitotic blocker, which can be mobilized under neuregulin-1 stimulation in vitro and in vivo. Mechanistically, the post-mitotic state of the adult CM relies on ephrin-B1 sequestering of inactive phospho-Yap1, the effector of the Hippo-pathway, at the lateral membrane. Hence, ephrin-B1 repression leads to phospho-Yap1 release in the cytosol but CM quiescence at resting state. Upon cardiac stresses (apectomy, MI, senescence), Yap1 could be activated and translocated to the nucleus to induce proliferation-gene expression and consequent CM proliferation. Conclusions: Our results identified ephrin-B1 as a new natural locker of adult CM proliferation and emphasize that targeting ephrin-B1 may prove a future promising approach in cardiac regenerative medicine for HF treatment.

How perennial organisms adapt to environments is a key question in biology. To address this question, we investigated ten natural black poplar (Populus nigra) populations from Western Europe, a keystone forest tree of riparian ecosystems. We assessed the role of (epi)genetic regulation in driving tree species evolution and adaptation over several millions of years (macro-evolution) up to a few generations (micro-evolution). At the macro-evolution scale, polar experienced differential structural (gene loss) and regulation (expression and methylation) reprogramming between sister genomic compartments inherited from polyploidization events. More interestingly, at the micro-evolution scale, both genetic and epigenetic variations differentiate populations from different geographic origins, targeting specifically genes involved in disease resistance, immune response, hormonal and stress response that can be considered as key functions of local adaptation of long lifespan species. Moreover, genes involved in cambium formation, an important functional trait for forest trees, as well as basal functions for cell survival are constitutively expressed though methylation control. These results highlight DNA methylation as a marker of population differentiation, evolutionary adaptation to diverse ecological environments and ultimately opening the need to take epigenetic marks into account in breeding strategies, especially for woody plants.