Project description:The lymphoid branch of the immune defense is composed of innate and adaptive immune cells. Using multiple genetic strategies we demonstrate that in the thymus E2A and HEB act in synergy to establish T cell identity and to suppress the aberrant development of innate lymphoid cells that include ILC2 and LTi-like cells. We found that E2A and HEB induce T cell fate by activating the expression of an ensemble of genes encoding for proteins associated with Notch- and pre-TCR signaling and to promote TCRβ antigen receptor assembly. We show that E2A and HEB act in early T progenitors (ETPs) to establish and maintain a T-lineage specific enhancer repertoire, including regulatory elements associated with the Notch1/3 and Rag1/2 gene loci. Based on these and previous observations we propose that the E-Id protein axis specifies innate versus adaptive lymphoid cell fate.
Project description:The lymphoid branch of the immune defense is composed of innate and adaptive immune cells. Using multiple genetic strategies we demonstrate that in the thymus E2A and HEB act in synergy to establish T cell identity and to suppress the aberrant development of innate lymphoid cells that include ILC2 and LTi-like cells. We found that E2A and HEB induce T cell fate by activating the expression of an ensemble of genes encoding for proteins associated with Notch- and pre-TCR signaling and to promote TCRβ antigen receptor assembly. We show that E2A and HEB act in early T progenitors (ETPs) to establish and maintain a T-lineage specific enhancer repertoire, including regulatory elements associated with the Notch1/3 and Rag1/2 gene loci. Based on these and previous observations we propose that the E-Id protein axis specifies innate versus adaptive lymphoid cell fate.
Project description:Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been studied extensively in model organisms, little is known about these âfirst respondersâ in humans, especially their lineage and functional kinships to cytokine-secreting T helper cell (Th) counterparts. Here, we report gene regulatory circuitries for four human ILCâTh counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells, but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell identity genes in each lineage, uncovering new modes of regulation for signature cytokines, novel molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILCâTh subsets. Molecular profiling of innate lymphoid and T helper cells subsets purified from tonsils and NK cells purified from peripheral blood using Assay for Transposase-Accessible Chromatin (ATAC) and chromatin immunoprecipitation (H3K4me3 and H3K27ac).
Project description:The type 2 helper effector program is driven by the master transcription factor GATA3 and can be expressed by subsets of both innate lymphoid cells (ILCs) and adaptive CD4+ T helper (Th) cells. While ILC2s and Th2 cells acquire their type 2 differentiation program under very different contexts, the distinct regulatory mechanisms governing this common program are only partially understood. Here we show that the differentiation of ILC2s, and their concomitant high level of GATA3 expression, are controlled by a Gata3 enhancer, Gata3 +674/762, that plays only a minimal role in Th2 cell differentiation. Mice lacking this enhancer exhibited defects in several but not all type 2 inflammatory responses, depending on the respective degree of ILC2 and Th2 cell involvement. Our study provides molecular insights into the different gene regulatory pathways leading to the acquisition of the GATA3-driven type 2 helper effector program in innate and adaptive lymphocytes.
