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.
2025-08-25 | GSE237401 | GEO
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.
2018-11-17 | GSE122624 | GEO
Project description:RORγt -expressing FOXP3+ skin-resident Treg cells derived from the periphery in Allergen-Specific Immunotherapy
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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.
2014-12-31 | GSE60059 | GEO
Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. DNA binding of RORγt in WT Th17 cells and under chemical perturbations of RORγt; Additional data is included for epitope-tagged exogenous RORγt in EL4 cells (a murine lymphoma cell line)
2014-04-17 | E-GEOD-56019 | biostudies-arrayexpress
Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Transcriptional profiling of Th17 cells under chemical perturbations of RORγt, DMSO, and knockout of RORγt. It includes repeats for all the data in GSE56018, plus one additional condition.
2014-04-17 | E-GEOD-56240 | biostudies-arrayexpress
Project description:Group 3 innate lymphoid cells (ILC3) are defined by the expression of RORγt, which is selectively required for their development. The lineage-specified progenitor cells of human ILC3 and their developmental site after birth remain undefined. Here we identified a novel population of human CD34+ hematopoietic progenitor cells (HPC) expressing RORγt and sharing with ILC3 a distinct transcriptional signature. RORγt+ CD34+ HPC were located in tonsils and intestinal lamina propria (LP) and selectively differentiated towards ILC3. Conversely, RORγt- CD34+ HPC displayed commitment potential for both ILC3 and NK cells and the differentiation fate towards these two cell lineages was determined by cytokine and aryl hydrocarbon receptor (AhR) signaling. Thus, we propose that RORγt+ CD34+ cells represent human lineage-specified progenitors of IL-22+ ILC3 and that tonsils as well as intestinal LP might be preferential sites of their differentiation.
2014-11-25 | GSE63197 | GEO
Project description:Retinoic-acid receptor-related orphan receptor-γt-positive (RORγt+) innate lymphoid cells (ILCs) produce interleukin (IL)-22 and IL-17, which are critical for protective immunity against enteric pathogens. The molecular mechanism underlying the development and survival of RORγt+ ILCs is not thoroughly understood. Here we show that Dedicator of cytokinesis 8 (DOCK8), a scaffolding protein involved in cytoskeletal rearrangement and cell migration, is essential for the protective immunity against Citrobacter rodentium. A comparative RNA sequencing-based analysis reveals an impaired induction of antimicrobial peptides in the colon of DOCK8-deficient mice, which correlates with high susceptibility to infection and a very low number of IL-22-producing RORγt+ ILCs in their GI tract. Furthermore, DOCK8-deficient RORγt+ ILCs are less responsive to IL-7 mediated signaling, more prone to apoptosis and produce less IL-22 due to a defect in IL-23-mediated STAT3 phosphorylation. Our studies reveal an unsuspected role of DOCK8 for the function, generation and survival of RORγt+ ILCs. Control and DOCK8 KO mice were infected with 2X109 CFU of Citrobacter rodentium and day 8 post infection mice were sacrificed and their colons were harvested (n=5) . Total RNA was purified from the infected colons with RNeasy mini kit (Qiagen). RNA sequencing was performed (pooled RNA sample from five mice in each group) at Genomic Core Facility Southwestern Medical Center, University of Texas.
2014-06-25 | E-GEOD-58765 | biostudies-arrayexpress
Project description:Invariant natural killer T cells (iNKT) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) and producing IL-17 represent a minor subset of CD1d-restricted iNKT cells (iNKT17) in C57BL/6J (B6) mice. We aimed in this study to define the reasons for their low distribution and the sequence of events accompanying their normal thymic development. We found that RORγt+ iNKT cells have higher proliferation potential and a greater propensity to apoptosis than RORγt- iNKT cells. These cells do not likely reside in the thymus indicating that thymus emigration, and higher apoptosis potential, could contribute to RORγt+ iNKT cell reduced thymic distribution. Ontogeny studies suggest that mature HSAlow RORγt+ iNKT cells might develop through developmental stages defined by a differential expression of CCR6 and CD138 during which RORγt expression and IL-17 production capabilities are progressively acquired. Finally, we found that RORγt+ iNKT cells perceive a strong TCR signal that could contribute to their entry into a specific Th17 like developmental program influencing their survival and migration. Overall, our study proposes a hypothetical thymic developmental sequence for iNKT17 cells, which could be of great use to study molecular mechanisms regulating this developmental program.
2019-10-19 | GSE139084 | GEO
Project description:RORγt+ innate lymphoid cells (ILC) are crucial players of innate immune responses and represent a major source of IL-22, which has an important role in mucosal homeostasis. The signals required by RORγt+ ILC to express IL-22 and other cytokines, including TNF, have only partially been elucidated. Here we show that RORγt+ ILC can directly sense the environment by the engagement of the activating receptor NKp44. NKp44 triggering in RORγt+ ILC selectively activates a coordinated pro-inflammatory program, including TNF, while cytokine stimulation induces preferentially IL-22 expression. However, combined engagement of NKp44 and cytokine receptors results in a strong synergistic effect. These data support the concept that NKp44+ RORγt+ ILC can be activated without cytokines and are able to switch between IL-22 or TNF production, depending on the triggering stimulus.
2013-10-30 | GSE43409 | GEO