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: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.
Project description:Non-lymphoid tissues (NLTs) harbour a pool of adaptive immune cells distinct from their counterparts in lymphoid tissues, and their development and phenotype remains largely unexplored. We used scRNA-seq to survey CD4+ T regulatory (Treg) and memory T (Tmem) cells in spleen, lymph nodes, skin and colon in an unbiased way, in mouse and human. This cross-tissues, cross-species comparison allows us to obtain marker genes for immune populations in specific locations with likely relevance for human studies. Additionally, a continuous phenotype of Treg migration can be modelled from the mouse data, unravelling the transcriptional stages through which these cells transition between tissues.
Project description:Natural killer (NK) cells are circulating lymphocytes that possess both innate and adaptive features, the latter including antigen-specific clonal expansion and long-lived memory responses. Unlike other adaptive lymphocytes like T and B cells, NK cells are not thought to require priming in lymphoid organs during activation. However, although NK cells respond in multiple tissue sites during cytomegalovirus (CMV) infection, here we observed that early activation and virus-specific expansion occurs predominantly in the spleen. These splenic NK cells exhibited heightened TNF-a signaling, which we identify as a novel and critical regulator of both innate and adaptive responses through engagement of distinct NF-kB signaling arms downstream of TNFR2. These findings highlight the central role of the spleen as a lymphoid organ in facilitating the innate-to-adaptive transition NK cells undergo during viral infection, and provide insight into how we can better generate innate and adaptive NK cell immunity across diverse settings. Bulk RNA-Seq data of WT or TNFR2-/- Ly49H+ NK from spleen at different time points post MCMV infection.