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Differentiation of T-regulatory type 1 cells into an immunoregulatory Foxp3+ subset distinct from conventional FoxP3+ T-regulatory cells

ABSTRACT: T-regulatory type-1 (TR1) cells are a subset of interleukin-10-producing but FoxP3-negative Treg cells that arise in vivo in response to chronic antigenic stimulation. We have shown that repetitive systemic delivery of autoimmune disease-relevant peptide-major histocompatibility complex class II (pMHCII)-coated nanoparticles (pMHCII-NP) triggers the formation of large pools of disease-suppressing Foxp3– TR1 cells from cognate T-follicular helper (TFH) cell precursors. Here we show that these Foxp3– TR1 cells spontaneously differentiate into a novel immunoregulatory Foxp3+ TR1 subset that inherits transcriptional and epigenetic hallmarks of their precursors and is distinct from other Foxp3+ Treg cell subsets described to date. Development of this novel Foxp3+ Treg cell subset, as is also the case for Foxp3– TR1 cells but not conventional Foxp3+ Treg cells, is BLIMP1-dependent. In a model of central nervous system autoimmunity, deletion of Il10 in the Foxp3+ TR1 subset, but not its FoxP3+ counterpart, reduces the therapeutic activity of pMHCII-NPs without impairing their pharmacodynamic activity. T cell-specific deletion of Prdm1 and deletion of Il10 in both the FoxP3– and FoxP3+ TR1 subsets almost completely abrogate the therapeutic activity of these compounds. Thus, the TFH-TR1 transdifferentiation pathway evolves through 4 distinct cellular states that culminate in the generation of IL-10-producing FoxP3– and FoxP3+ TR1 subsets in a BLIMP1-dependent manner. This transdifferentiation pathway represents a new target for therapeutic intervention in immunity and autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE252235 | GEO | 2025/02/26

REPOSITORIES: GEO

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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.

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Differentiation of T-regulatory type 1 cells into an immunoregulatory Foxp3+ subset distinct from conventional FoxP3+ T-regulatory cells

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