A Crohn’s Disease-associated IL2RA Enhancer Variant Determines the Balance of T Cell Immunity by Regulating Responsiveness to IL-2 Signalling

• DOI: 10.1093/ecco-jcc/jjab103
• Publication Date: 2021-06-10T19:16:38Z
• Authors: Rimma Goldberg; Jennie N Clough; Luke B Roberts; Jenifer Sanchez; Shahram Kordasti; Nedyalko Petrov; Arnulf Hertweck; Anna Lorenc; Ian Jackson; Scott Tasker; Anna Appios; Omer Omer; Miles Parkes; Natalie Prescott; Richard G Jenner; Peter M Irving; Graham M Lord
• Keywords: CD4-Positive T-Lymphocytes; Male; 0301 basic medicine; 570; Databases, Factual; Interleukin-2 Receptor alpha Subunit; 610; Original Articles; Middle Aged; Polymorphism, Single Nucleotide; T-Lymphocytes, Regulatory; State Medicine; United Kingdom; Immunophenotyping; 3. Good health; 03 medical and health sciences; Crohn Disease; Case-Control Studies; Humans; Interleukin-2; Female; Signal Transduction

Abstract

Background and Aims Differential 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.

Methods Teff 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.

Results Presence 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.

Conclusions rs61839660 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.