Type 1 Diabetes-Associated <i>IL2RA</i> Variation Lowers IL-2 Signaling and Contributes to Diminished CD4+CD25+ Regulatory T Cell Function

Garg, Garima; Tyler, Jennifer R; Yang, Jennie H.M.; Cutler, Antony J.; Downes, Kate; Pękalski, Marcin Ł.; Bell, Gwynneth L.; Nutland, Sarah; Peakman, Mark; Todd, John A.; Wicker, Linda S.; Tree, Timothy

doi:10.4049/jimmunol.1100272

Cited by 178 publications

(156 citation statements)

References 46 publications

(54 reference statements)

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“…Other studies have reported associations between common noncoding polymorphisms at the IL2RA locus and susceptibility to several autoimmune diseases (37)(38)(39), probably through an impairment of Treg cell responses (40). Genetic variants in the IL2 and IL2RB regions have also been associated with immune dysregulation (41)(42)(43).…”

Section: Foxp3mentioning

confidence: 99%

IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

Oliveira

Dessein

Romano

et al. 2015

The Journal of Immunology

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The outcome of Leishmania infections varies substantially, depending on the host and the parasite strain; infection may be asymptomatic or cause mild or severe skin ulcers (cutaneous leishmaniasis [CL]), limited or disseminated lesions, or lethal visceral disease. We previously reported an association between IL-2R mutations and susceptibility to visceral leishmaniasis in children infected with Leishmania donovani. In the present study, we evaluated the possible role of IL-2 signaling in human CL. We first showed that the transcripts of several genes of the IL-2 pathway were abundant in skin lesions caused by Leishmania braziliensis. We then carried out a genetic analysis, focusing on major genes of the IL-2 pathway. We used a family-based approach and found that polymorphisms of several genes appeared to be associated with CL in a Brazilian population. Moreover, two polymorphisms of the IL2RA gene were significantly and independently associated with CL. We confirmed this result in a second Brazilian sample (also exposed to L. braziliensis) and in Iranians infected with Leishmania tropica: IL2RA rs10905669 T (Pcombined = 6 × 10−7) and IL2RA rs706778 T (Pcombined = 2 × 10−9) were associated with greater susceptibility to lesion development. These alleles were also correlated with a poor IFN-γ response and poor FOXP3+ regulatory T cell activation. Thus, IL-2 plays a crucial role in protection against the cutaneous ulcers caused by Leishmania, and the IL-2 pathway is a potential target for strategies aiming to control Leishmania-related diseases.

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Section: Foxp3mentioning

confidence: 99%

IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

Oliveira

Dessein

Romano

et al. 2015

The Journal of Immunology

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“…Initially associated with T1D susceptibility using a candidate gene and tag SNP approach [15], further studies revealed association to other autoimmune diseases, including MS [16] and rheumatoid arthritis [17], and demonstrated that multiple genetic markers were needed to explain the T1D association [18]. Genotype to phenotype studies have demonstrated that disease-associated variants in the region also associate with IL2RA mRNA expression and CD25 protein expression on the surface of naive and memory CD4 + T cells [19][20][21] and sensitivity of memory CD4 + T and activated T regulatory cells to IL-2 [22].…”

Section: Introductionmentioning

confidence: 99%

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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“…Thus, the availability of IL-2 in the local environment has significant consequences for the development and homeostasis of the Tfh population. These findings may be relevant to the observed increase in Tfh in type 1 diabetes, as multiple defects in the IL-2 signalling pathway have been associated with this disease setting [132][133][134][135][136]. Interestingly Kenefeck et al found an inverse relationship between the ability of T cells from type 1 diabetes patients to respond to IL-2 and propensity to acquire a Tfh phenotype in vitro [106].…”

Section: Il-2 Signalling Impairs Tfh Differentiationmentioning

confidence: 96%

CD4 T cell differentiation in type 1 diabetes

Walker

Herrath

2015

Clinical and Experimental Immunology

146

101

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SummarySusceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

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Type 1 Diabetes-Associated IL2RA Variation Lowers IL-2 Signaling and Contributes to Diminished CD4+CD25+ Regulatory T Cell Function

Cited by 178 publications

References 46 publications

IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis

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

CD4 T cell differentiation in type 1 diabetes

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