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Adaptive plasticity of IL10 + and IL35 + regulatory T cells

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE127735 | GEO | 2019/04/02

REPOSITORIES: GEO

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Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

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

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Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

Project description:Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

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Project description:Mouse monocytes exposed to M-CSF and IFN-γ were driven to a suppressor phenotype over a seven day culture period. The resulting regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarised macrophages and monocyte-derived DCs. M regs completely suppressed polyclonal T cell proliferation through an inducibile nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs were found to eliminate cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5x10^6 donor-strain M regs prior to transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c and C57BL/6-to-BALB/c strain combinations; this graft-protective effect was alloantigen-specific. M regs from Nos2-deficient mice did not prolong allograft survival, proving that M reg function in vivo is iNOS-mediated and dependent on living cells. Co-treatment with 1 mg/kg/day rapamycin for 10 days post-transplant markedly enhanced the effect of M regs. In untransplanted C57BL/6 recipients, M regs of BALB/c origin were detectable for up to 2 weeks post-infusion. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of tolerogenic macrophages, which resemble human M regs in their derivation, phenotype and in vitro functions.

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Project description:Mouse monocytes exposed to M-CSF and IFN-M-NM-3 were driven to a suppressor phenotype over a seven day culture period. The resulting regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarised macrophages and monocyte-derived DCs. M regs completely suppressed polyclonal T cell proliferation through an inducibile nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs were found to eliminate cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5x10^6 donor-strain M regs prior to transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c and C57BL/6-to-BALB/c strain combinations; this graft-protective effect was alloantigen-specific. M regs from Nos2-deficient mice did not prolong allograft survival, proving that M reg function in vivo is iNOS-mediated and dependent on living cells. Co-treatment with 1 mg/kg/day rapamycin for 10 days post-transplant markedly enhanced the effect of M regs. In untransplanted C57BL/6 recipients, M regs of BALB/c origin were detectable for up to 2 weeks post-infusion. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of tolerogenic macrophages, which resemble human M regs in their derivation, phenotype and in vitro functions. The dataset comprises 36 samples divided into twelve sample groups each representing a certain monocyte/macrophage subtype

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regulatory T cells in human pregnancy

Project description:Transplacental immune programming refers to the concept that during pregnancy, significant crosstalk occurs between the maternal and fetal immune system, with consequent long‐term effects especially for the offspring. In this study, we searched for evidence of transplacental programming in cellular immunity. We made the surprising observation that there is a stringent and specific correlation of regulatory T cells (Treg) between the mother and the fetus. Gene microarray analysis indicates that interleukin 10 (IL‐10) might be involved in transplacental Treg alignment. This is further supported by the direct correlation of IL‐10 at a protein level between maternal fetal dyads. In vitro data provide evidence that IL‐10 may regulate the homeostatic balance between Tregs and non‐Tregs through selective upregulation of the anti‐apoptotic molecule Bcl‐2 in Tregs. Induction of IL‐10 might be triggered by fetus‐derived estriol (E3), which readily crosses the placenta and correlates with maternal IL‐ 10 levels. Our study represents the first example of transplacental regulation of cellular immunity between the mother and the fetus. These novel findings might have major implications for pregnancy related‐changes in the maternal and fetal immune system, and provide possible mechanistic insights into how prenatal influences can lead to subsequent immunopathologies, such as allergy and autoimmunity. T-reg and non-Treg samples of non pregnant women, and matched cord blood and maternal blood T-regs and non-T-regs

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