Adaptive plasticity of IL10 + and IL35 + regulatory T cells
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ABSTRACT:
PROVIDER: PRJNA525180 | ENA |
REPOSITORIES: ENA
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Project description:Regulatory T cells (T regs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. T regs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; Ebi3/IL12α heterodimer) are divergently expressed by T reg subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. T reg -restricted deletion of Il10 and/or Ebi3 resulted in delayed tumor growth, loss of multi-IR expression, and reduced intratumoral CD8 + T cell exhaustion signature. While Il10 or Ebi3 loss was associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1), IL10 and IL35 differentially impacted effector versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for IL10 and IL35, produced by limits effective anti-tumor immunity
2019-04-02 | GSE127735 | GEO
Project description:Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion
| PRJNA521251 | ENA
Project description:Abstract: Regulatory T cells (Tregs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Tregs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; a heterodimer of Ebi3 and IL12) are reciprocally expressed by Treg-subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. Treg-restricted deletion of either Il10/Ebi3 or dual deletion resulted in delayed tumor growth and significant reduction of transcriptomic exhaustion signature associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1). While the two cytokines share the BLIMP1 axis to drive multi-IR expression; they differentially impact effector vs. memory fate, highlighting their overlapping and non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated adaptive plasticity in inhibitory cytokine expression pattern by Tregs in TME for maximal immunosuppression. Data purpose: to understand the segregated cytokine expression pattern and the preferential generation of single cytokine positive Treg subpopulations, we performed single cell RNASeq (scRNAseq) contrasting Tregs isolated from naïve, unchallenged LNs or day 14 B16 tumor from Foxp3Cre-YFP WT mice
2019-04-02 | GSE126184 | GEO
Project description:Maternal IL10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here we show that Il10 null mutant (Il10-/-) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4+ and CD8+ T cells compared with wild-type controls. Amongst these CD4+ cells, Foxp3+ Treg cells were substantially enriched, with 11-fold higher numbers at day 9.5 post coitum (pc). Lymph node hypertrophy in Il10-/- mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10-/- mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2 and Ifng. In vitro, Il10-/- Treg cells showed reduced steady state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4+Foxp3- T cells. We conclude that despite a substantially expanded Treg cell pool, diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10-/- mice. These findings suggest a pivotal role for IL10 in facilitating robust immune protection of the fetus from inflammatory challenge and suggest IL10 deficiency could contribute to human gestational disorders where altered T cell responses are implicated. RNA was extracted from CD4+CD25+ lymphocytes isolated from para-aortic LNs of day 9.5 pc pregnant Il10+/+ or Il10-/- mice using miRNeasy Mini Kits (Qiagen Inc., Valencia, CA, USA) according to the manufacturer’s instructions. The concentration and purity of each RNA sample was determined using the Nanodrop Spectrophotometer (ND-1000, Nanodrop Technologies Inc., Wilmington, DE). RNA quality was determined using the RNA 6000 Pico Total RNA Kit (Agilent Technologies, Santa Clara CA) prior to use in microarray experiments. RNA with a RIN>7 was used in this study. For microarray analysis, RNA was pooled (from 2-4 mice per pool) resulting in four biological replicates of CD4+CD25+ cells from both Il10-/- and Il10+/+ mice. Microarray analysis was performed using Affymetrix Mouse Gene 2.0 ST Arrays at the Adelaide Microarray Centre. Total RNA was amplified using the Ovation PicoSL WTA System V2 (Nugen Inc., San Carlos, CA, USA) and MinElute Reaction Cleanup Kit (Qiagen Inc., Valencia, CA, USA), according to the manufacturer’s instructions, to provide 5 ?g of cRNA for each microarray. The microarray data was normalized and analyzed using Partek Genomics Suite (Partek Inc, MO). Raw data from the Affymetrix platform (.cel files) were imported and normalized using RMA background correction, Partek’s own GC content correction, and mean probe summarization.
2015-07-30 | E-GEOD-71494 | biostudies-arrayexpress
Project description:Maternal IL10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here we show that Il10 null mutant (Il10-/-) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4+ and CD8+ T cells compared with wild-type controls. Amongst these CD4+ cells, Foxp3+ Treg cells were substantially enriched, with 11-fold higher numbers at day 9.5 post coitum (pc). Lymph node hypertrophy in Il10-/- mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10-/- mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2 and Ifng. In vitro, Il10-/- Treg cells showed reduced steady state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4+Foxp3- T cells. We conclude that despite a substantially expanded Treg cell pool, diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10-/- mice. These findings suggest a pivotal role for IL10 in facilitating robust immune protection of the fetus from inflammatory challenge and suggest IL10 deficiency could contribute to human gestational disorders where altered T cell responses are implicated.
2015-07-30 | GSE71494 | GEO
Project description:The interplay between phenotypic plasticity and adaptive evolution has long been an important topic of evolutionary biology. This process is critical to our understanding of a species evolutionary potential in light of rapid climate changes. Despite recent theoretical work, empirical studies of natural populations, especially in marine invertebrates, are scarce. In this study, we investigated the relationship between adaptive divergence and plasticity by integrating genetic and phenotypic variation in Pacific oysters from its natural range in China. Genome resequencing of 371 oysters revealed unexpected fine-scale genetic structure that is largely consistent with phenotypic divergence in growth, physiology, thermal tolerance and gene expression across environmental gradient. These findings suggest that selection and local adaptation are pervasive and together with limited gene flow shape adaptive divergence. Plasticity in gene expression is positively correlated with evolved divergence, indicating that plasticity is adaptive and likely favored by selection in organisms facing dynamic environments such as oysters. Divergence in heat response and tolerance implies that the evolutionary potential to a warming climate differs among oyster populations. We suggest that trade-offs in energy allocation are important to adaptive divergence with acetylation playing a role in energy depression under thermal stress.
2018-07-27 | PXD008057 | Pride
Project description:Distinct Gene Regulatory Pathways for Human Innate Versus Adaptive Lymphoid Cells
| PRJNA314321 | ENA
Project description:IL-27 is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, Atf3) and 2 negative (Irf9, Irf8) Il10 regulators, generating an experimentally refined regulatory network for Il10. We report two central regulators Prdm1 and Maf that cooperatively drive the expression of signature genes induced by IL-27 in Type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3+regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying the ll10 deficient mice. Our work provides insights for IL-27 driven transcriptional networks and identifies two shared Il10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.
2020-12-21 | GSE158703 | GEO
Project description:The safety and efficacy(IL10 expression level) of a recombinant adeno-associated virus derivative (rAAVr3.45) were examined to evaluate its potential as a gene carrier for preparing interleukin-10 (IL10)-secreting human neural stem cells (HFT13) that can treat ischemic injuries or neurodegenerative diseases.
2017-05-18 | GSE99032 | GEO
Project description:Regulatory T cells (Tregs) can suppress a wide variety of cell types, in diverse organ sites and inflammatory conditions. While Tregs possess multiple suppressive mechanisms, the number required for maximal function is unclear. Furthermore, whether any inter-relationship orcross-regulatory mechanisms exist that areused to orchestrate and control their utilization is unknown. Here we assessed the functional capacity of Tregs lacking the ability to secrete both interleukin-10 (IL-10) and IL-35, which individually are required for maximal Treg activity. Surprisingly, IL-10/IL-35-double deficient Tregswere fully functionalin vitro and in vivo. Loss of IL-10 and IL-35 was compensated for by a concurrent increase in cathepsin E (CTSE) expression, enhanced TRAIL (Tnfsf10)expression and soluble TRAIL release, rendering IL-10/IL-35-double deficient Tregsfunctionally dependent on TRAIL in vitro and in vivo. Lastly, while C57BL/6 Tregs are IL-10/IL-35-dependent, Balb/c Tregs, which express high levels of CTSE and enhanced TRAIL expression, are TRAIL-dependent.These data reveal that cross-regulatory pathways exist, which control the utilization of suppressive mechanisms,thereby providing Tregfunctional plasticity. Isolate natural Tregs from the different knockout mouse
2011-12-08 | E-GEOD-29262 | biostudies-arrayexpress