Adult thymus-derived cMaf+RORγt+γδ T cells lack Scart2 chromatin accessibility and do not reach periphery
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PROVIDER: PRJNA994892 | ENA |
REPOSITORIES: ENA
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Project description:T cell receptor (TCR) Vγ4+expressing γδT cells can be divided into IFN-γ and IL-17-producing effector T cell subsets. A bias towards γδ17 effector fate decisions is observed during early ontogeny. In contrast, the existence of Vγ4+γδ17 cells derived from adult thymus is still controversial. In the present work, we used a mouse model where T cells are exclusive generated within an adult thymus. Additionally, we employed single-cell chromatin state analysis from thymocytes of normal mice. A small, but considerable population of immatureCd24+Gzma+Vγ4 cells was found that exhibit molecular programs of γδ17 cells. These adult thymus-derived immatureCd24a+cMaf+Vγ4 cells secrete small amounts of IL-17A and IL-17F. Interestingly, do not reach the periphery under steady-state conditions. Furthermore,de novogenerated γδ17-like cells from adult thymus lack transcriptional activity of the Scart2 encoding gene, suggesting that Scart2 is a distinct trait of fetal γδT cell precursors. Together, this study provides valuable insights into developmental traits of Vγ4 cells during adulthood and raises the question on signals suppressing the full maturation and/or thymic export of γδ17-like cells within the adult thymus.
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Project description:Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but how they contribute to disorders such as SpA is still unclear. Here we describe the presence of particular RORγt+T-betloPLZF- iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt+ iNKT and γδ-hi T cells showed profound IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed a unique Th17 skewed phenotype and gene expression profile. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, these findings highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.
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Project description:This study investigates the post-thymic maturation and transcriptional programming of intestinal γδ T cells across early life. Single-cell RNA sequencing of FACS-sorted small-intestinal lamina propria γδ T cells was performed at four developmental stages: newborn, day 7, day 21, and post-weaning (day 42) in order to characterize dynamic changes in cell composition, activation, and effector programs. Mice carried a RORγt-Cre allele, cIAP1 floxed alleles, and a full cIAP2 knockout. Both Cre⁺ and Cre⁻ γδ T cells were sorted; Cre⁻ cells served as wild-type controls and were used to define the normal developmental trajectory (aim 1), while Cre⁺ cells, which lack cIAP proteins, were analyzed alongside their Cre⁻ littermates controls to determine how cIAP deficiency affects γδ T cell development and transcriptional profile (aim 2).
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Project description:Foxp3-expressing regulatory (Treg) T cells are essential for immunological tolerance, where loss of this transcription factor leads to uncontrolled T cell responses and their associated clinical presentation of systemic autoimmunity in mice and humans. Importantly, Foxp3+ Tregs result from different origins and are either generated in the thymus (tTreg) or from conventional CD4+ T cells in the periphery (pTreg). In addition, Treg cells may adopt specific effector Treg phenotypes, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3+ T cells expressing the Th17 master transcription factor, RORγt, represent a stable effector Treg lineage that is specifically enriched in intestinal organs and gut-associated lymphoid tissues in mice possessing a complex microbial microflora. Simultaneous expression of Foxp3 and RORγt promotes the transcription of both Treg- and Th17-associated genes in Foxp3+RORγt+ T cells; however, epigenetic profiling of the Treg-specific demethylated region (TSDR) and other Treg-associated genes revealed a high degree of similarity between conventional Tregs and Foxp3+RORγt+ T cells, indicating that these cells have a stable regulatory, rather than inflammatory, function. Indeed, adoptive transfer of Foxp3+RORγt+ T cells in the context of T cell transfer colitis not only confirmed their Treg function and lineage stability in vivo, it also revealed a significantly enhanced regulatory capacity as compared to RORγt+ Treg cells. Thus, our data suggest that RORγt expression in Tregs is essential for optimal regulation of gut-specific immune responses, which renders them an important effector Treg lineage in the intestinal system.
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Project description:Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cMAF as a key transcription factor for brain perivascular macrophages. Conditional deletion of cMAF disrupts the phenotype of perivascular macrophages, while sparing microglia. Functionally, cMAF drives IGF1 expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer’s Disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communications with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.
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Project description:Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cMAF as a key transcription factor for brain perivascular macrophages. Conditional deletion of cMAF disrupts the phenotype of perivascular macrophages, while sparing microglia. Functionally, cMAF drives IGF1 expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer’s Disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communications with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.
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Project description:Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cMAF as a key transcription factor for brain perivascular macrophages. Conditional deletion of cMAF disrupts the phenotype of perivascular macrophages, while sparing microglia. Functionally, cMAF drives IGF1 expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer’s Disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communications with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF providing evidence that this program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for cerebrovascular and neurodegenerative diseases.
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Project description:Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cMAF as a key transcription factor for brain perivascular macrophages. Conditional deletion of cMAF disrupts the phenotype of perivascular macrophages, while sparing microglia. Functionally, cMAF drives IGF1 expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer’s Disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communications with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.
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