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The effect of 1-Oleoyl-lysophosphatidylethanolamine (LPE) on the RORgt activity in Th17 cells

ABSTRACT: Th17 cells are a helper cell subset of pro-inflammatory T cells, which have diverse functions ranging from neutrophilic-inflammatory responses against pathogens to driving a number of autoimmune diseases. Accumulating evidence indicates that specific cellular lipid metabolic pathways that include fatty acid or cholesterol play an essential role in regulating the differentiation and function of Th17 cells. However, what molecular mechanisms link lipid metabolism and RORgt function during Th17-cell differentiation? By using a combination of a CRISPR- based screening system and a global lipidome analysis, we addressed this question in an effort to identify a specific lipid metabolite that is essential for RORgt-mediated Th17-cell differentiation. We found five lipid enzymes that elicit RORgt activity and constitute a core molecular signature of Th17 cells. Furthermore, although Th17 cells treated with TOFA, which is a ACC1 inhibitor, showed decreased mRNA expression of Th17 specific gene and chromatin accessibility at Th17 cell specific gene loci, we also found that extrinsic supplementation of LPE (1-18:1) restored the phenotype of ACC1-inhibited Th17 cells. Taken together, these series of results indicated that LPE (1-18:1) synthesized from the five lipid metabolic enzymes was required for RORgt to function appropriately in Th17-cell differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE230624 | GEO | 2023/05/08

REPOSITORIES: GEO

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Project description:The mutualistic relationship of gut-resident microbiota and cells of the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a poised, but largely non-aggressive, immune cell compartment1. Consequences of disturbing this balance, by environmental or genetic factors, include proximal inflammatory conditions, like Crohn’s disease, and systemic illnesses, both metabolic and autoimmune. One of the means by which this equilibrium is achieved is through induction of both effector and suppressor or regulatory arms of the adaptive immune system. In mice, Helicobacter species induce regulatory (iTreg) and follicular helper (Tfh) T cells in the colon-draining mesenteric lymph nodes under homeostatic conditions, but can instead induce inflammatory Th17 cells when iTreg cells are compromised3,4. How Helicobacter hepaticus and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here, we investigated which cells and molecular components are required to convey the microbial instruction for the iTreg differentiation program. We found that antigen presentation by cells expressing RORgt, rather than by classical dendritic cells, was both required and sufficient for iTreg induction. These RORgt+ cells, likely to be type 3 innate lymphoid cells (ILC3) or a recently-described population of Aire+ cells termed Janus cells5, require the MHC class II antigen presentation machinery, the chemokine receptor CCR7, and av integrin, which activates TGF-β, for iTreg cell differentiation. In the absence of any of these, instead of iTreg cells there was expansion of microbiota-specific pathogenic Th17 cells, which were induced by other antigen presenting cells (APCs) that did not require CCR7. Thus, intestinal commensal microbes and their products target multiple APCs with pre-determined features suited to directing appropriate T cell differentiation programs, rather than a common APC that they endow with appropriate functions.

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The effect of 1-Oleoyl-lysophosphatidylethanolamine (LPE) on the RORgt activity in Th17 cells

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