Abstract
Background and AimsDifferential responsiveness to interleukin [IL]-2 between effector CD4+ T cells [Teff] and regulatory T cells [Treg] is a fundamental mechanism of immunoregulation. The single nucleotide polymorphism [SNP] rs61839660, located within IL2RA [CD25], has been associated with the development of Crohn’s disease [CD]. We sought to identify the T cell immune phenotype of IBD patients who carry this SNP.MethodsTeff and Treg were isolated from individuals homozygous [TT], heterozygous [CT], or wild-type [CC] for the minor allele at rs61839660, and used for phenotyping [flow cytometry, Cytometry Time Of Flight] functional assays or T cell receptor [TCR] sequencing. Phosphorylation of signal transducer and activator of transcription 5 [STAT5] was assessed in response to IL-2, IL-7, and in the presence of basiliximab, a monoclonal antibody directed against CD25. Teff pro-inflammatory cytokine expression levels were assessed by reverse transcription quantitative polymerase chain reaction after IL-2 and/or TCR stimulation.ResultsPresence of the minor T allele enhances CD25 expression, leading to increased STAT5 phosphorylation and pro-inflammatory cytokine transcript expression by Teff in response to IL-2 stimulation in vitro. Teff from TT individuals demonstrate a more activated gut homing phenotype. TCR sequencing analysis suggests that TT patients may have a reduced clonal capacity to mount an optimal regulatory T cell response.Conclusionsrs61839660 regulates the responsiveness of T cells to IL-2 signalling by modulating CD25 expression. As low-dose IL-2 is being trialled as a selective Treg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype.
Highlights
Crohn’s disease [CD] is a complex immune-mediated disorder with polygenic inheritance, in which inappropriate activation of the intestinal immune system in a genetically susceptible individual triggers chronic inflammation of the gastrointestinal tract
We propose that the reduced ratio of Treg:Teff CD25 expression in individuals homozygous [TT] for this SNP may increase the ability of Teff to respond to low environmental IL-2, permitting activation of Teff at levels of IL-2 which would usually only activate Treg
We show that rs61839660 enhances IL-2 signalling in CD4+ T cells from CD patients by regulating the expression of CD25
Summary
Crohn’s disease [CD] is a complex immune-mediated disorder with polygenic inheritance, in which inappropriate activation of the intestinal immune system in a genetically susceptible individual triggers chronic inflammation of the gastrointestinal tract. The value of a personalised approach to treatment is increasingly recognised, with the aim of targeting a treatment at the dominant aberrant pathway in a given patient to maximise efficacy and minimise side effects.[3] The IL-2 pathway has been identified as potentially therapeutically tractable in numerous autoimmune conditions, including inflammatory bowel disease [IBD], with recruitment to a trial of low-dose IL-2 in CD under way [ClinicalTrials.gov NCT01988506]. Regulatory [Treg] and effector [Teff] CD4+ T cells are important mediators of the immune response in the gut of IBD patients, with defects in Treg number and suppressive function noted in the lamina propria and peripheral blood of patients with active IBD.[4,5] many identified IBD genetic risk loci map to immune cell enhancer regions, with particular enrichment in CD4+ T cell enhancers.[6] Treg are characterised by high constitutive expression of the IL-2 receptor alpha chain [IL2RA, CD25], a component of the highaffinity IL-2 receptor heterotrimer [IL2Rα/β/γ]. We sought to define the immune phenotype associated with rs61839660 in CD patients, with the aim of understanding potential therapeutic targets in this patient cohort
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