Cells with Treg-specific<i>FOXP3</i>demethylation but low CD25 are prevalent in autoimmunity

Ferreira, Ricardo C.; Simons, Henry Z.; Thompson, Whitney S.; Rainbow, Daniel B.; Yang, Xin; Cutler, Antony J.; Oliveira, João J.; Dopico, Xaquín Castro; Smyth, Deborah J.; Savinykh, Natalia; Mashar, Meghavi; Vyse, Tim J.; Baxendale, Helen; Chandra, Anita; Wallace, Chris; Todd, John; Wicker, Linda S.; Pękalski, Marcin Ł.

doi:10.1101/134692

Cited by 21 publications

(29 citation statements)

References 29 publications

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“…To address this question, we initially profiled the expression of 397 genes at the mRNA level, coupled with 37 protein targets (Table S1) using the AbSeq technology [11] in CD4 + T cells isolated from blood of a systemic lupus erythematosus (SLE) patient. To enrich for the relative distribution of two less abundant CD4 + T-cell subsets: (i) CD127 low CD25 + T cells, containing the Treg population; and (ii) CD127 low CD25 low T cells, containing a subset of non-conventional CD25 low FOXP3 + Tregs previously characterised in autoimmune patients [12], we devised a FACSsorting strategy to isolate and profile equal numbers of cells from the three defined T-cell subsets ( Fig. 1a).…”

Section: Simultaneous Protein Quantification Increases the Power Of Smentioning

confidence: 99%

Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Trzupek

Dunstan

Cutler

et al. 2019

Preprint

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The transcriptomic and proteomic characterisation of CD4 + T cells at the single-cell level has been performed traditionally by two largely exclusive types of technologies: single cell RNAsequencing (scRNA-seq) technologies and antibody-based cytometry. Here we demonstrate that the simultaneous targeted quantification of mRNA and protein expression in single-cells provides a high-resolution map of human primary CD4 + T cells, and reveals precise trajectories of Th1, Th17 and regulatory T-cell differentiation in blood and tissue. We report modest correlation between mRNA and protein in primary CD4 + T cells at the single-cell level, highlighting the value of protein expression data to characterise cell effector function. This transcriptomic and proteomic hybrid technology provides a massively-parallel, cost-effective, solution to dissect the heterogeneity of immune cell populations and to immunophenotype rare and potentially pathogenic immune subsets, and could have important clinical applications to redefine differentiation and activation of circulating and tissue-resident human immune cells.

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Section: Simultaneous Protein Quantification Increases the Power Of Smentioning

confidence: 99%

Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Trzupek

Dunstan

Cutler

et al. 2019

Preprint

Self Cite

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“…Studies addressing peripheral blood Treg frequencies in patients with T1D have produced somewhat conflicting results, with studies reporting increased , decreased , or similar frequencies of Tregs in patients with T1D compared to healthy controls. The highly variable approaches to define Tregs in different studies make direct comparison of these results challenging.…”

Section: Introductionmentioning

confidence: 99%

Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells

et al. 2019

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Dysfunction of FOXP3‐positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D‐associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non‐HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody‐positive at‐risk subjects, and 215 islet autoantibody‐negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10−6) and naïve (p = 4 × 10−5) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody‐negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.

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“…Treg cell subpopulations within the mLN and colon tissue are analogous to those we have recently described in mouse 26 . We also identify an additional population, termed Treg-like cells, reminiscent of a CD25 - FOXP3 lo PD1 hi Treg population in the peripheral blood, although the latter was described to also express Ki67 44 . This population could represent uncommitted Treg cells experiencing transient loss of FOXP3 while retaining regulatory potential 27 or permanent loss FOXP3 and adoption of a more pro-inflammatory phenotype after repeated stimulation 45 .…”

Section: Discussionmentioning

confidence: 91%

Distinct microbial and immune niches of the human colon

James

Gomes

Elmentaite

et al. 2019

Preprint

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42Gastrointestinal microbiota and immune cells interact closely and display regional 43 specificity, but little is known about how these communities differ with location. Here, 44we simultaneously assess microbiota and single immune cells across the healthy, 45 adult human colon, with paired characterisation of immune cells in the mesenteric 46 lymph nodes, to delineate colonic immune niches at steady-state. We describe 47 distinct T helper cell activation and migration profiles along the colon and 48 characterise the transcriptional adaptation trajectory of T regulatory cells between 49 lymphoid tissue and colon. Finally, we show increasing B cell accumulation, clonal 50 expansion and mutational frequency from caecum to sigmoid colon, and link this to 51 the increasing number of reactive bacterial species. 52 53

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Cells with Treg-specificFOXP3demethylation but low CD25 are prevalent in autoimmunity

Cited by 21 publications

References 29 publications

Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Discovery of CD80 and CD86 as recent activation markers on regulatory T cells by protein-RNA single-cell analysis

Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells

Distinct microbial and immune niches of the human colon

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