Thymic mesenchymal niche cells drive T cell immune regeneration

Abstract

Thymic atrophy and the progressive immune decline that accompanies it is a major health problem, chronically with age and acutely with immune injury. No solution has been defined. Here we demonstrate that one of the three mesenchymal cell subsets identified by single-cell analysis of human and mouse thymic stroma is a critical niche component for T lymphopoiesis. The Postn+ subset is located perivascularly in the cortical-medullary junction, medulla and subcapsular regions. Cell depletion demonstrated that it recruits T competent cells to the thymus and initiates T lymphopoiesis in vivo. This subset distinctively expresses the chemokine Ccl19 necessary for niche functions. It markedly declines with age and in the acute setting of hematopoietic stem cell transplant conditioning. When isolated and adoptively transferred, these cells durably engrafted the atrophic thymus, recruited early T progenitors, increased T cell neogenesis, expanded TCR complexity and enhanced T cell response to vaccination. These data define a thymus lymphopoietic niche cell type that may be manipulated therapeutically to regenerate T lymphopoiesis.

Sex biased human thymic architecture guides T cell development through spatially defined niches

“…Importantly, we enriched and captured 7721 mesenchymal cells, a population that has recently been highlighted for newly described roles in negative selection and thymic involution 9,19,[34][35][36] . Subclustering of this population revealed several important mesenchymal cell types including two populations of endothelial cells (ECs) defined by differential expression of Notch ligands JAG1, JAG2, DLL1, and DLL4 (ECs, ECs (Notch)).…”

“…The thymic tissue dissociation protocol detailed by Gustafson et al was used to enrich for CD45cells 9 . Briefly, a 1 cm 3 tissue section was crushed using a syringe in a small petri dish.…”

“…Recent single cell sequencing resources demonstrating the diversity of human thymus tissue are incongruous with our current framework of thymus structure and organization [7][8][9][10][11][12][13][14][15][16][17][18][19] which describes a general migratory path a thymocyte takes through the cortex and medulla during conventional αβT cell development. Recent spatial transcriptomic sequencing of human fetal and postnatal thymus has demonstrated that a deeper granularity of thymic niches is present within the tissue and that these niches evolve during fetal development to support different waves of non-conventional T cells 19,20 .…”