IL7R is required for hematopoietic stem cell reconstitution of tissue-resident lymphoid cells

Traditional, adult-derived lymphocytes that circulate provide adaptive immunity to infection and pathogens. However, subsets of lymphoid cells are also found in non-lymphoid tissues and are called tissue-resident lymphoid cells (TLCs). TLCs encompass a wide array of cell types that span the spectrum of innate-to-adaptive immune function. Unlike traditional lymphocytes that are continuously generated from hematopoietic stem cells (HSCs), many TLCs are of fetal origin and poorly generated from adult HSCs. Here, we sought to understand the development of murine TLCs across multiple tissues and therefore probed the roles of Flk2 and IL7R, two cytokine receptors with known roles in traditional lymphopoiesis. Using Flk2- and Il7r-Cre lineage tracing models, we found that peritoneal B1a cells, splenic marginal zone B (MZB) cells, lung ILC2s and regulatory T cells (Tregs) were highly labeled in both models. Despite this high labeling, highly quantitative, in vivo functional approaches showed that the loss of Flk2 minimally affected the generation of these cells in situ. In contrast, the loss of IL7R, or combined deletion of Flk2 and IL7R, dramatically reduced the cell numbers of B1a cells, MZBs, ILC2s, and Tregs both in situ and upon transplantation, indicating an intrinsic and more essential role for IL7R. Surprisingly, reciprocal transplants of WT HSCs showed that an IL7R-/- environment selectively impaired reconstitution of TLCs when compared to TLC numbers in situ. Taken together, our data revealed functional roles of Flk2 and IL7R in the establishment of tissue-resident lymphoid cells.