Multiple Autoimmune-Associated Variants Confer Decreased IL-2R Signaling in CD4+CD25hi T Cells of Type 1 Diabetic and Multiple Sclerosis Patients

Cerosaletti, Karen; Schneider, Anya; Schwedhelm, Katharine V.; Frank, Ian; Tatum, Megan; Wei, Shan; Whalen, Elizabeth; Greenbaum, Carla J.; Kita, Mariko; Buckner, Jane H.; Long, S. Alice

doi:10.1371/journal.pone.0083811

Cited by 103 publications

(102 citation statements)

References 41 publications

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“…Several studies in autoimmune patients have reported that even modest changes in CD25 expression modify IL-2 sensitivity and greatly influence Treg function (26,27). In the present study we observed diminished CD25 expression, reduced sensitivity to low concentrations of IL-2, and increased cell apoptosis in Tregs from transplant recipients receiving tacrolimus therapy.…”

Section: Discussionsupporting

confidence: 64%

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Whitehouse

Gray

Mastoridis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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+ Tregs constitute a heterogeneous lymphocyte subpopulation essential for curtailing effector T cells and establishing peripheral tolerance. Calcineurin inhibitors (CNIs) are among the most effective agents in controlling effector T-cell responses in humans. However, CNIs also reduce the size of the Treg pool. The functional consequences of this negative effect and the mechanisms responsible remain to be elucidated. We report here that CNIs compromise the overall Treg immunoregulatory capacity to a greater extent than would be predicted by the reduction in the size of the Treg compartment, given that they selectively promote the apoptosis of the resting and activated Treg subsets that are known to display the most powerful suppressive function. These effects are caused by reduced access to IL-2, because Tregs remain capable of translocating NFAT even in the presence of high CNI levels. Exogenous IL-2 restores the phenotypic changes and overall gene-expression effects exerted by CNIs and can even promote Treg expansion by enhancing antiapoptotic Bcl-2 expression. In a skin transplant model, the addition of IL-2 synergizes with CNIs treatment, promoting intragraft accumulation of Tregs and prolonged allograft survival. Hence, the combination of IL-2 and CNIs constitutes an optimal immunomodulatory regimen that enhances the pool of suppressive Treg subsets while effectively controlling cytopathic T cells.regulatory T cells | transplantation | IL-2 therapy | calcineurin inhibitors |

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Section: Discussionsupporting

confidence: 64%

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Whitehouse

Gray

Mastoridis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This emphasises the need for surveying the most complete set of variants possible in order to make cross disease comparisons. Variants in this region have previously been linked to several aspects of IL-2R signalling in T1D and MS patients [27] and the MS-associated variants we identify (whether under the M1 or M2 models) all showed some evidence of association with expression of CD25 on the surface of T cells, linking IL2RA in a primary way into the etiology of this disease. For T1D, we were only able to link the IL2RA intron 1 signal, shared with MS under the M1 model, to CD25 expression on memory T cells.…”

Section: Discussionmentioning

confidence: 61%

Dissection of a complex disease susceptibility region using a Bayesian stochastic search approach to fine mapping

Wallace

Cutler

Pontikos

et al. 2015

Preprint

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Identification of candidate causal variants in regions associated with risk of common diseases is complicated by linkage disequilibrium (LD) and multiple association signals. Nonetheless, accurate maps of these variants are needed, both to fully exploit detailed cell specific chromatin annotation data to highlight disease causal mechanisms and cells, and for design of the functional studies that will ultimately be required to confirm causal mechanisms. We adapted a Bayesian evolutionary stochastic search algorithm to the fine mapping problem, and demonstrated its improved performance over conventional stepwise and regularised regression through simulation studies. We then applied it to fine map the established multiple sclerosis (MS) and type 1 diabetes (T1D) associations in the IL-2RA (CD25) gene region. For T1D, both stepwise and stochastic search approaches identified four T1D association signals, with the major effect tagged by the single nucleotide polymorphism, rs12722496. In contrast, for MS, the stochastic search found two distinct competing models: a single candidate causal variant, tagged by rs2104286 and reported previously using stepwise analysis; and a more complex model with two association signals, one of which was tagged by the major T1Dassociated rs12722496 and the other by rs56382813. There is low to moderate LD between rs2104286 and both rs12722496 and rs56382813 (r 2 ⋍ 0:3) and our two SNP model could not be recovered through a forward stepwise search after conditioning on rs2104286. Both signals in the two variant model for MS affect CD25 expression on distinct subpopulations of CD4 + T cells, which are key cells in the autoimmune process. The results support a shared causal variant for T1D and MS. Our study illustrates the benefit of using a purposely designed model search strategy for fine mapping and the advantage of combining disease and protein expression data. Author SummaryGenetic association studies have identified many DNA sequence variants that associate with disease risk. By exploiting the known correlation that exists between neighbouring variants in the genome, inference can be extended beyond those individual variants tested to identify sets within which a causal variant is likely to reside. However, this correlation, particularly in the presence of multiple disease causing variants in relative proximity, makes disentangling the specific causal variants difficult. Statistical approaches to this fine mapping problem have traditionally taken a stepwise search approach, beginning with the most associated variant in a region, then iteratively attempting to find additional associated variants. We adapted a stochastic search approach that avoids this stepwise process and is explicitly designed for dealing with highly correlated predictors to the fine mapping problem. We showed in simulated data that it outperforms its stepwise counterpart and other variable selection strategies such as the lasso. We applied our approach to understand the association of two immune-mediated dis...

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“…Horizontal bars represent means, with SD as error bars; statistical analysis between Tregs and Tconvs by one-way ANOVA with Sidák multiple comparisons test. ****P # 0.0001. with changes in Treg function (24)(25)(26)(27)(28)(29), so future studies to correlate changes in the Treg signature with genetic risk factors are warranted.…”

Section: Discussionmentioning

confidence: 99%

A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes

et al. 2016

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Type 1 diabetes (T1D) is caused by immune-mediated destruction of insulin-producing β-cells. Insufficient control of autoreactive T cells by regulatory T cells (Tregs) is believed to contribute to disease pathogenesis, but changes in Treg function are difficult to quantify because of the lack of Treg-exclusive markers in humans and the complexity of functional experiments. We established a new way to track Tregs by using a gene signature that discriminates between Tregs and conventional T cells regardless of their activation states. The resulting 31-gene panel was validated with the NanoString nCounter platform and then measured in sorted CD4+CD25hiCD127lo Tregs from children with T1D and age-matched control subjects. By using biomarker discovery analysis, we found that expression of a combination of six genes, including TNFRSF1B (CD120b) and FOXP3, was significantly different between Tregs from subjects with new-onset T1D and control subjects, resulting in a sensitive (mean ± SD 0.86 ± 0.14) and specific (0.78 ± 0.18) biomarker algorithm. Thus, although the proportion of Tregs in peripheral blood is similar between children with T1D and control subjects, significant changes in gene expression can be detected early in disease process. These findings provide new insight into the mechanisms underlying the failure to control autoimmunity in T1D and might lead to a biomarker test to monitor Tregs throughout disease progression.

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Multiple Autoimmune-Associated Variants Confer Decreased IL-2R Signaling in CD4+CD25hi T Cells of Type 1 Diabetic and Multiple Sclerosis Patients

Cited by 103 publications

References 41 publications

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

Dissection of a complex disease susceptibility region using a Bayesian stochastic search approach to fine mapping

A Regulatory T-Cell Gene Signature Is a Specific and Sensitive Biomarker to Identify Children With New-Onset Type 1 Diabetes

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