Embryonic thymocyte-epithelial cell crosstalk plays an essential role in the establishment of adult T cell tolerance 2068

Description During gestation, the thymus is colonized by a first wave of thymic seeding progenitors (TSP) with the unique capacity to generate invariant γδ T cells and lymphoid tissue inducer (LTi) cells. Interaction between these embryonic populations and medullary (m) thymic epithelial cells (TEC) induces, in the later, expression of autoimmune regulator (AIRE), essential for negative selection of self-reactive T cells, at a restricted developmental window. Mice with reduced progenies of the first wave of TSP can be obtained by injecting anti-IL7Rα Ab into pregnant females. These mice (rTSP1) either died before 9 months of age (50%) or exhibited severe immune infiltrates in multiple organs and strong thymic involution. At postnatal day (P)15, rTSP1 mice showed reduced thymic regulatory T cells but normal numbers of other thymocyte populations. Unlike control mice, which showed a peak of mTEC at P30, rTSP1 mice maintained constant mTEC numbers throughout life. Transcriptional analyses of TEC in rTSP1 mice at P30 showed a virtual absence of AIRE-expressing mTEC and fewer immature and FOXN1-expressing mTEC. Thymi from rTSP1 mice persistently displayed small medullary areas that failed to coalesce. Sublethally irradiated or dexamethasone-treated rTSP1 mice failed to regenerate their TEC compartment and exhibited delayed thymocyte recovery. Thus, embryonic thymocyte-TEC interactions are essential for normal adult thymic function, and disruption results in lifelong immune effects. Funding Sources Supported by ANR; REVIVE; Institut Pasteur. Topic Categories Basic Autoimmunity (BA)