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Surface CD69-negative bone-marrow resident human memory T cells [ESR transcription]

ABSTRACT: Across tissues, tissue-resident memory T cells have been defined as cells which express CD69 in their cell surface, but not S1PR1, the receptor for the tissue-egress signal sphingosin-1-phosphate (S1P). It is less clear whether CD69-negative memory T cells are also tissue-resident. Here, we compare transcriptomes and T cell receptor repertoires of individual CD4 and CD8 memory T cells from paired blood and bone marrow of three human donors. CD69- memory T cells of blood and bone marrow share transcriptionally defined clusters, as defined by signature genes reflecting their imprinting during activation. However, cells of related clusters of blood and bone marrow have distinct TCR repertoires, suggesting that they represent distinct compartments of memory, and that the CD69- memory T cells are residents of the bone marrow. Interestingly, the surface CD69- memory T cells of bone marrow do transcribe the CD69 gene, and they express S1PR1, suggesting that they are blindfolded for S1P by dimerization and internalization of CD69 and S1PR1, maintaining them in the tissue.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278283 | GEO | 2025/05/21

REPOSITORIES: GEO

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Project description:Background: Myeloid cells (MCs) reside in the aortic intima at regions predisposed to atherosclerosis. Systemic inflammation triggers reverse transendothelial migration (RTM) of intimal MCs into arterial blood, which orchestrates a protective immune response that clears intracellular pathogens from the arterial intima. Molecular pathways that regulate RTM remain poorly understood. Sphingosine-1-phosphate (S1P) is a lipid mediator that regulates immune cell trafficking by signaling via five G protein-coupled receptors (S1PRs). We investigated the role of S1P in the RTM of aortic intimal MCs. Methods: Intravenous injection of lipopolysaccharide (LPS) was used to model a systemic inflammatory stimulus that triggers RTM. CD11c+ intimal MCs in the lesser curvature of the ascending aortic arch were enumerated by en face confocal microscopy. Local gene expression was evaluated by transcriptomic analysis of microdissected intimal cells. Results: In wild-type C57BL/6 mice, LPS induced intimal cell expression of S1pr1, S1pr3, and sphingosine kinase 1 (Sphk1, a kinase responsible for S1P production). Pharmacological modulation of multiple S1PRs blocked LPS-induced RTM and modulation of S1PR1 and S1PR3 reduced RTM in an additive manner. Cre-mediated deletion of S1pr1 in MCs blocked LPS-induced RTM, confirming a role for myeloid-specific S1PR1 signaling. Global or hematopoietic deficiency of Sphk1 reduced plasma S1P levels, the abundance of CD11c+ MCs in the aortic intima and blunted LPS-induced RTM. In contrast, plasma S1P levels, the abundance of intimal MCs, and LPS-induced RTM were rescued in Sphk1-/- mice transplanted with Sphk1+/+ or mixed Sphk1 +/+ and -/- bone marrow. Stimulation with LPS increased endothelial permeability and intimal MC exposure to circulating factors such as S1P. Conclusions: Functional and expression studies support a novel role for S1P signaling in the regulation of LPS-induced RTM as well as the homeostatic maintenance of aortic intimal MCs. Our data provides insight into how circulating plasma mediators help orchestrate intimal MC dynamics.

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Surface CD69-negative bone-marrow resident human memory T cells [ESR transcription]

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