c-Myb is required for the development of innate lymphoid cells (ILCs) 3271

Description Innate lymphoid cells (ILCs) arise in the bone marrow from the Common Lymphoid Progenitor (CLP), and are divided in two major groups, cytotoxic ILCs (NKs) and helper ILCs. To test the role of c-Myb in the development of ILCs, we generated c-Mybf/f;IL7Rα-Cre mice. These mice showed major decreases in ILC numbers and percentages in all measured organs (Bone marrow, lung. liver, lamina propria). In contrast, NK cells were less affected, and most of the reduction in this lineage was in mature NKs. Importantly, the effect on ILCs was already complete in c-Mybf/+;IL7Rα-Cre, suggesting that even partial reduction in c-Myb expression is limiting for the development of ILCs. We then analyzed early ILC and NK precursors in the bone marrow. We did not observe any alteration in NK precursors, but there was a major block at the ILCP stage in ILCs. c-Mybº ILCPs fail to upregulate GATA-3, but expression of Id2 or Tcf7 is not affected. However, overexpression of GATA-3 failed to rescue ILC development, suggesting that c-Myb has additional targets in this process. ATAC-Seq analysis of sorted ILC progenitors showed that c-Mybº precursors have decreased chromatin accessibility across a number of loci, enriched for genes involved in lymphoid development. Our results suggest that c-Myb levels in CILPs are rate limiting, and small changes bias the choice between NK and ILC differentiation, probably by regulating chromatin accessibility across genes important for ILC development. Funding Sources Supported by Oklahoma Center for Sdult Stem Cell Research, NIH/GM P30 GM149376 Topic Categories Hematopoiesis and Immune System Development (HEM)