Project description:Innate lymphoid cells (ILC) are tissue-resident effector cells with important roles in tissue homeostasis, protective immunity and inflammatory disease. Here we investigated the role of the transcription factor Bcl6 in small intestinal innate lymphoid cells. Specifically, we performed single-cell RNA-seq on total small intestine lamina propria ILCs from tamoxifen-treated Id2-CreERT2 ROSA26-tdRFP Bcl6-fl/fl mice and Id2-CreERT2 ROSA26-tdRFP controls.
Project description:Interleukin-(IL) 22 production by intestinal group 3 innate lymphoid cells (ILC3) is critical to maintain gut homeostasis. However, IL-22 needs to be tightly controlled; reduced IL-22 expression is associated with intestinal epithelial barrier defect while its overexpression promotes tumor development. Here, using a single cell RNAseq approach, we identified a core set of genes associated with increased IL-22 production by ILC3.
Project description:Group 3 innate lymphoid cells (ILC3s) play crucial roles in maintaining intestinal homeostasis and defending against bacterial infections. However, the epigenetic mechanisms that regulate ILC3 responses are not well understood. In this study, we show that Trmt61a, the methyltransferase responsible for the m1A58 tRNA modification, is predominantly expressed in ILC3s. We found that specific depletion of TRMT61A in ILC3s leads to dysregulated cell cycle and a reduction in cell numbers. Notably, mice with an ILC3-specific TRMT61A deficiency exhibit dysbiosis, but antibiotic treatment can restore colonic ILC3 levels. Furthermore, these mice exhibit increased susceptibility to experimental intestinal inflammation and enteric bacterial infection. Our findings uncover a previously unrecognized role for TRMT61A mediated m1A modification in the regulation of intestinal ILC3s, essential for protecting intestinal tissue during inflammation and enhancing innate immunity against enteric pathogens.
Project description:Neuro-immune circuits regulate innate and adaptive immunity at barrier surfaces, however the differential impact of these circuits on proinflammatory versus tissue-protective responses remains poorly defined. We identify that enteric neurons produce CGRP-related adrenomedullin 2 (ADM2), and identify a previously unrecognized role for the ADM2-ADM2 receptor pathway in promoting intestinal tissue-protective functions of group 2 innate lymphoid cells (ILC2s). Genomic or ILC2-intrinsic deletion of ADM2 receptor subunits resulted in a significant reduction in tissue-protective ILC2 responses, defective amphiregulin (AREG) production and increased susceptibility to intestinal damage and inflammation. Conversely, therapeutic delivery of recombinant ADM2 elicited tissue-protective AREG production in ILC2s and limited intestinal inflammation. Expression of genes encoding human ADM2 receptor (CALCRL and RAMP3) was altered in IBD patients and associated with reduced expression of AREG in ILC2s. Collectively, these findings identify that the ADM2-ADM2 receptor pathway can promote tissue-protective functions of ILC2s in the context of intestinal damage and inflammation.
Project description:Group 3 Innate Lymphoid Cells (ILC3s) is important for maintaining intestinal homeostasis and host defense. Emerging studies have shown that metabolic regulation plays a crucial role in regulating ILC3 activation and function. However, the role of Liver Kinase B1 (LKB1), key metabolic regulator, in regulating ILC3 function and intestinal immunity remains poorly understood. In this study, we show that LKB1 is essential for ILC3 postnatal development, effector function, and intestinal immunity. Ablation of LKB1 in ILC3s results in reduced cell number due to increased apoptosis and reduced proliferation, which occurs at 2 -3 weeks after birth. In addition, LKB1 deletion leads to diminished IL-22 production and less protection against C.rodentium infection. Mechanistically, LKB1 deficiency led to impaired mitochondrial metabolism, as indicated by reduced glycolysis and oxidative phosphorylation and less mitochondrial mass. Together, our data demonstrate that LKB1 promotes ILC3 postnatal development and effector function to maintain intestinal immune homeostasis.
Project description:Small intestinal group 3 innate lymphoid cells (ILC3) from ILC3-conditional BMAL1 knock out mice or littermate control mice were sort-purified for transcriptional analysis
Project description:Innate lymphoid cells (ILC) in the small intestine govern immune homeostasis and protect the host against gut pathogens. While distinct cell-intrinsic signals have been identified that determine ILC development and differentiation, it has remained unclear which cell population regulates ILC sustenance. Using unbiased single cell RNA transcriptomic analysis of intestinal fibroblasts, we have identified a specialized Ccl19-expressing fibroblastic reticular cell (FRC) population that underpins solitary intestinal lymphoid tissue (SILT) structures including cryptopatches and isolated lymphoid follicles. Conditional ablation of lymphotoxin-β receptor (LTβR) signalling in SILT FRC impeded the maturation of isolated lymphoid follicles and blocked ILC maintenance through the downregulation of IL-7, consequently resulting in the elevated susceptibility to bacterial infection. Moreover, specific Ltbr ablation in FRC during adulthood revealed that constant LTβR-dependent FRC-ILC interaction is required to maintain SILT structures and ILC populations. Taken together, our study unveils a critical intestinal FRC niche that secures protective gut immunity.
