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Hepatic leukemia factor directs tissue residency of proinflammatory CD4+ T cells [bulk]

ABSTRACT: Hepatic leukemia factor directs tissue residency of proinflammatory CD4+ T cells [bulk]

PROVIDER: PRJNA1255174 | ENA |

REPOSITORIES: ENA

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Hepatic leukemia factor directs tissue residency of proinflammatory CD4+ T cells

Project description:CD4+ tissue-resident memory T cells (TRM) contribute to both host defense and pathogenesis of chronic inflammatory diseases. However, the molecular mechanisms that direct tissue residency and functional heterogeneity of CD4+ TRM remain unknown. We herein show that the transcription factor, hepatic leukemia factor (HLF), directs the tissue residency program and functionality of CD4+ TRM. HLF simultaneously upregulates tissue retention receptors and downregulates tissue egress receptors via changes in chromatin accessibility, and drives proinflammatory CD4+ TRM by inducing Bhlhe40. Genetic deletion of Hlf inhibits CD4+ TRM generation, consequently ameliorating airway tissue inflammation in vivo. In humans, HLF-positive CD4+ TRM from inflamed airway tissue have a tissue residency signature and express inflammatory cytokines. HLF is therefore a central regulator of proinflammatory CD4+ TRM development and function.

2025-07-04 | GSE295436 | GEO

Hepatic leukemia factor directs tissue residency of proinflammatory CD4+ T cells [bulk]

2025-07-04 | GSE295553 | GEO

Hepatic leukemia factor directs tissue residency of proinflammatory CD4+ T cells

Project description:Hepatic leukemia factor directs tissue residency of proinflammatory CD4+ T cells

| PRJNA1254670 | ENA

Runx3 drives a tissue residency program that is absent in CD4+ T cells [ATAC-seq]

Project description:Tissue-resident memory T (TRM) cells provide rapid and superior control of localized infections. The transcription factor Runx3 was recently identified as a master regulator of CD8+ T cell tissue residency. However, Runx3 also drives CD8+ T cell lineage commitment and is repressed in CD4+ T cells, raising the possibility that this transcription factor defines a form of tissue residency unique to the CD8+ T cell subset. Here, we show that as a direct consequence of Runx3-deficiency, CD4+ TRM cells in epithelia lack the TGFb-responsive transcriptional network that underpins CD8+ TRM cell residency. Ectopic Runx3 expression in CD4+ T cells rescued this transcriptional program to promote prolonged survival, decreased tissue egress and a microanatomical redistribution towards epithelial layers that combined, resulted in superior local immune protection. Our results thus reveal a mechanistic discordance between CD4+ and CD8+ TRM cell formation in barrier tissues that is controlled by Runx3. Consequently, CD4+ TRM cells are unable to adopt a type of tissue residency that is intrinsically accessible to the CD8+ TRM cell subset.

2022-05-24 | GSE198611 | GEO

Runx3 drives a tissue-residency program that is absent in CD4+ T cells [RNA-seq]

Project description:Pattens of tissue-residency differs between CD4+ and CD8+ memory T cells in evironmentally exposed organs. The lineage-controlling transcription factor Runx3, expressed in CD8+ T cells, is responsible for shaping a tissue-resident gene network in response to the cytokine TGF-b. While the lack of Runx3 by CD4+ T cells precludes these transcriptional changes, Runx3-overexpression in CD+ T cells enable phenotypical, transcriptional and functional changes to allow residency.

2022-05-24 | GSE182511 | GEO

Runx3 drives a tissue-residency program that is absent in CD4+ T cells

Project description:Runx3 drives a tissue-residency program that is absent in CD4+ T cells

| PRJNA816144 | ENA

STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis

Project description:STAT1 deficiency underlies a proinflammatory imprint of naive CD4+ T cells in spondyloarthritis

| PRJNA1026882 | ENA

Runx3 drives a tissue residency program that is absent in CD4+ T cells [ATAC-seq]

Project description:Runx3 drives a tissue residency program that is absent in CD4+ T cells [ATAC-seq]

| PRJNA816148 | ENA

Runx3 drives a tissue-residency program that is absent in CD4+ T cells [RNA-seq]

Project description:Runx3 drives a tissue-residency program that is absent in CD4+ T cells [RNA-seq]

| PRJNA756546 | ENA

HIF-2a drives hepatic Kupffer cell death and liver inflammation in nonalcoholic steatohepatitis

Project description:Proinflammatory activation of hepatic macrophages plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the placement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that HIF-2a mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2a stimulated mTOR and ERK-dependent inhibitory TFEB phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2a-dependent TFEB regulation only occurred in KCs, but not in RHMs. Instead, in RHMs, HIF-2a promoted mtROS production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Taken together, our results suggest that macrophage subtype-specific effects of HIF-2a collectively contributes to the proinflammatory activation of liver macrophages, leading to the development of NASH.

2025-05-06 | PXD040457 | Pride

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