BATF regulates innate lymphoid cell hematopoiesis and homeostasis

Abstract

Abstract Early hematopoietic progenitors undergo sophisticated developmental processes to become committed progenitors for innate lymphoid cells (ILC) in hematopoietic tissues, which ultimately become mature ILC subsets in the periphery. Basic leucine zipper ATF-like transcription factor (Batf) plays important roles in lymphocyte biology. We report that Batf regulates the production of bone marrow ILC progenitors and maintenance of peripheral ILCs. Batf is most highly expressed in ILCs among all lymphocytes. Data from in vivo and in vitro ILC differentiation experiments revealed that the expression of Batf is induced in early ILC progenitors at the α-lymphoid progenitor stage in response to the cytokine IL-7. Our Chromatin immunoprecipitation and retroviral gene transfer experiments revealed that up-regulated Batf binds and activates transcription of the Nfil3 gene to promote ILC hematopoiesis. Data from bone marrow chimera and parabiosis experiments support that Batf is intrinsically necessary to maintain normal numbers of early and late ILC progenitors in the bone marrow and mature ILC1, ILC2, ILC3, and NK cells in most peripheral tissues. Batf-deficient mice have ILC3 lymphopenia and fail to control Citrobacter rodentium infection. Moreover, ILC2 responses to cytokines were defective in Batf-deficient mice. Thus, Batf is required for normal ILC responses to inflammatory cytokines and bacterial infection. These data suggest that Batf plays fairly comprehensive roles in supporting bone marrow hematopoiesis, maintenance, and effector functions of ILCs.