RORγt inhibition selectively targets IL-17 producing human iNKT and γδ-T cells enriched in Spondyloarthritis while preserving IL-22 responses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA505801 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8199720.fastq.gz | Fastqsanger.gz | |||
| SRR8199730.fastq.gz | Fastqsanger.gz | |||
| SRR8199740.fastq.gz | Fastqsanger.gz | |||
| SRR8199721.fastq.gz | Fastqsanger.gz | |||
| SRR8199731.fastq.gz | Fastqsanger.gz |
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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.
2018-11-17 | GSE122624 | GEO
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:Characterization of the developmental landscape of murine RORγt+ iNKT cells
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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:We identified a novel subset of iNKT cells, C2 iNKT cells, that circulate in the periphery. Correspondingly, we characterized the tissue-resident iNKT cell subset, C1 iNKT cells. The development and terminal maturation of C2 iNKT cells completely depended on the thymic epithelial IL-15 niche, whereas C1 iNKT cells were regulated also by local IL-15 niches in peripheral tissues. C2 iNKT cells expressed high levels of genes related to cytotoxicity and exhibited more NK cell-like features. Functionally, C2 iNKT cells regulated self-antigen expression for immune tolerance in the thymus and mediated cancer immunosurveillance in the periphery.
2022-08-08 | GSE150813 | 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
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.
2014-06-25 | GSE58765 | GEO
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:We identified a novel subset of iNKT cells, C2 iNKT cells, that circulate in the periphery. Correspondingly, we characterized the tissue-resident iNKT cell subset, C1 iNKT cells. We also found the precursor of these two subsets of iNKT cells, C0 iNKT cells in thymus. The development and terminal maturation of C2 iNKT cells completely depended on the thymic epithelial IL-15 niche, whereas C1 iNKT cells were regulated also by local IL-15 niches in peripheral tissues. C2 iNKT cells expressed high levels of genes related to cytotoxicity and exhibited more NK cell-like features. Here we characterized the C2 iNKT cells, C1 iNKT cells, and C0 iNKT cells using RNA-seq. We also performed RNA-seq for CD4+ T cells, CD8+ T cells and NK cells as a comparison. To investigate the effect of CD4, we performed the RNA-seq for the CD4+ and CD4- C2 iNKT cells.
2022-08-08 | GSE206627 | GEO
Project description:TH17 cells play a critical role in mucosal immunity and also in multiple autoimmune diseases. The differentiation of TH17 cells is dictated by a master transcription factor, RORγt; however, the mechanism by which RORγt controls target genes is poorly understood. Here we identify the Swi/Snf chromatin remodeling complex as an essential regulator of TH17 cell differentiation. Loss of the expression of SRG3/mBAF155, a core subunit of the Swi/Snf complex, results in a specific downregulation of RORγt target genes such as IL-17A, IL-17F and IL-23R. Importantly, the comparative transcriptional analysis reveals a high similarity between RORγt and the Swi/Snf complex in the control of TH17-related gene expression. Mechanistically, the Swi/Snf complex partners with RORγt and coordinates a variety of RORγt–mediated epigenetic modifications, including both permissive and repressive ones. These results provide a basis for the understanding of how a master transcription factor RORγt cooperates with the Swi/Snf complex to govern the Th17 cell differentiation.
2020-05-06 | GSE129132 | GEO