EOMES‐positive CD4<sup>+</sup> T cells are increased in <i>PTPN22</i> (1858T) risk allele carriers

Chemin, Karine; Ramsköld, Daniel; Diaz-Gallo, Lina-Marcela; Herrath, Jessica; Houtman, Miranda; Tandre, Karolina; Rönnblom, Lars; Catrina, Anca I.; Malmström, Vivianne

doi:10.1002/eji.201747296

Cited by 37 publications

(58 citation statements)

References 64 publications

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“…Limited data in humans suggest that Treg cells from individuals homozygous for the PTPN22 rs2476601 A risk allele (AA genotype) display TCR signalling defects similar to those observed in conventional T cells [30]. No differences in circulating Treg frequencies in association with PTPN22 genotypes have been reported in two previous studies analysing small cohorts of adult subjects [30,31], although in line with our observation a tendency for higher Treg frequencies were observed in the group with the AA genotype in the latter study [31]. However, it is important to note that both of these studies have been underpowered compared to our study.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…To define the various T‐αβ subpopulations, a phenotype based on TCR‐αβ, CD4, and CD8 staining should be combined with CD183 (CXCR3; Th1 and Tc1), CD194 (CCR4) and CD294 (CRTH2; both for Th2 and Tc2), CD196 (CCR6) or CD161 (KLRB1; both for Th17 and Tc17), CCR10 (Th22), and CD25 (IL‐2Rα) and CD152 (CTLA4; both for CD4 + and CD8 + Tregs) (Table and Fig. ) . However, so far no distinct extracellular marker for Th9 and Tc9 cells has been identified.…”

Section: T‐αβ Cell Subsets Can Be Defined By Extracellular Proteins mentioning

confidence: 99%

“…For better discrimination, subsequent intracellular transcription factor profiling can be performed. These include T‐bet (Th/c1), GATA3 (Th/c2), PU.1 (Th9), RORγt (Th/c17), AHR, and/or FOXO4 (Th22) and FoxP3 (CD4/CD8 + Tregs) . Selective transcription factors for Tc9 have not yet been found.…”

Section: T‐αβ Cell Subsets Can Be Defined By Extracellular Proteins mentioning

confidence: 99%

“…Nevertheless, the best method to distinguish between the subsets is based on their cytokine secretion profile upon stimulation in the presence of a Golgi system inhibitor, like Brefeldin A or Monensin, to prevent cytokine release. Following subsequent fixation and permeabilization, cells can be stained for intracellular IFNγ and IL2 (Th1/Tc1), IL4 and IL5 (Th2/Tc2), IL9 (Th9/Tc9), IL10 (CD4 + /CD8 + Treg), IL17 (Th17/Tc17), and IL22 (Th22) .…”

Section: T‐αβ Cell Subsets Can Be Defined By Extracellular Proteins mentioning

confidence: 99%

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Comprehensive Phenotyping of T Cells Using Flow Cytometry

et al. 2019

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The T cell compartment can form a powerful defense against extrinsic (e.g., pathogens) and intrinsic danger (e.g., malignant cells). At the same time, specific subsets of T cells control this process to keep the immune system in check and prevent autoimmunity. A wide variety in T cell functionalities exists, which is dependent on the differentiation and maturation state of the T cells. In this review, we report an overview for the identification of CD4 + T-αβ cells (T-helper (Th)1, Th2, Th9, Th17, Th22, and CD4 + regulatory T cells), CD8 + T-αβ cells (cytotoxic T lymphocyte (Tc)1, Tc2, Tc9, Tc17, and CD8 + regulatory T cells), and their additional effector memory status (naïve, stem cell memory, central memory, effector memory, and effector) using flow cytometry. These different subsets can be discriminated based on selective extracellular markers, in combination with intracellular transcription factor and/or cytokine stainings. Additionally, identification of very small subsets, including antigen-specific T cells, and important technical considerations of flow cytometry are discussed. Together, this overview can be used for comprehensive phenotyping of a T cell subset of interest.

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“…Another possible effect of the PTPN22 1858 T allele on T cells is that found by a recent study, which reported that upon TCR‐activation, naïve human CD4+ T cells from homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4‐1BB , which are important for cytotoxic T‐cell differentiation. Moreover, they found an accumulation of a subgroup of CD4+ T cells producing perforin‐1 (EOMES+CD4+ T cells) in synovial fluid of RA patients in PTPN22 risk allele carriers, and these cells were proposed as a relevant T‐cell subset in RA pathogenesis. Altogether, these findings and ours provide novel mechanisms of action of the PTPN22 risk allele in RA.…”

Section: Discussionmentioning

confidence: 99%

PTPN22 1858C>T polymorphism is associated with increased CD154 expression and higher CD4+ T cells percentage in rheumatoid arthritis patients

Ruiz‐Noa

Hernández‐Bello

Llamas-Covarrubias

et al. 2018

Clinical Laboratory Analysis

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Background CD40 is a costimulatory molecule for B cells, and CD154 is a marker of CD4+ T cells activation. CD40‐CD154 interaction promotes pro‐inflammatory cytokines secretion and autoantibodies production. PTPN22 gene encodes LYP protein, an inhibitor of T‐ and B‐cell activation. PTPN22 1858C>T polymorphism confers rheumatoid arthritis (RA) susceptibility. Hence, we evaluate the relationship between 1858C>T polymorphism with CD40 and CD154 expression and IFN‐γ secretion in RA patients. Methods PTPN22 1858C>T polymorphism was genotyped in 315 RA patients and 315 control subjects (CS) using PCR‐RFLP method. Later, we selected only ten anti‐CCP‐positive RA patients, naïve to disease‐modifying antirheumatic drugs and ten CS, all with known 1858C>T PTPN22 genotype. The CD40 and CD154 membrane expressions were determined by flow cytometry in peripheral B and T cells, correspondingly. Results The B cells percentage and mCD40 expression were similar between RA and CS (P > 0.05) and we did not find an association between these variables and the 1858C>T polymorphism. The CD4+ T cells percentage was higher in RA patients than CS (P = 0.003), and in the RA group, the CD4+ T cells percentage and mCD154 expression were higher in the 1858 T allele carriers (P = 0.008 and P = 0.032, respectively). The IFN‐γ levels were lower in RA patients carrying the PTPN22 risk allele (P = 0.032). Conclusion The PTPN22 1858 T risk allele is associated with increased CD4+ T cells percentage and high mCD154 expression in RA patients, which could favor the pro‐inflammatory cytokine release and the establishment of the inflammatory response at the seropositive RA.

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EOMES‐positive CD4⁺ T cells are increased in PTPN22 (1858T) risk allele carriers

Cited by 37 publications

References 64 publications

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

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

Comprehensive Phenotyping of T Cells Using Flow Cytometry

PTPN22 1858C>T polymorphism is associated with increased CD154 expression and higher CD4+ T cells percentage in rheumatoid arthritis patients

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EOMES‐positive CD4+ T cells are increased in PTPN22 (1858T) risk allele carriers

Cited by 37 publications

References 64 publications

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

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

Comprehensive Phenotyping of T Cells Using Flow Cytometry

PTPN22 1858C>T polymorphism is associated with increased CD154 expression and higher CD4+ T cells percentage in rheumatoid arthritis patients

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EOMES‐positive CD4⁺ T cells are increased in PTPN22 (1858T) risk allele carriers