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

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 rs61839660, located within IL2RA (CD25), has been associated with the development of Crohn’s disease. 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 proinflammatory 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 proinflammatory 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 signaling by modulating CD25 expression. As low dose IL-2 is being trialed as a selective Treg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype.

Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency

“…rs1214598 is also in strong LD with SNPs associated with eczema [133] and autoimmune thyroid disease [134]. The SNP rs61839660 is located in intron 7 of IL2RA and is known for associations with multiple autoimmune [135] and atopic diseases including Crohn’s disease [136], type 1 diabetes [122], asthma and allergic disease [137], and eczema [138]. Loss-of-function mutations in IL2RA cause the autosomal recessive IEI CD25 deficiency, a disease of immune dysregulation featuring T regulatory cell defects, recurrent infection, lymphoproliferation, atopy, and autoimmunity [1,139,140].…”

ANANASTRA: annotation and enrichment analysis of allele-specific transcription factor binding at SNPs

“…Considering particular SNPs, there is rs61839660 located in the intron region of the IL2RA gene. The downregulated IL2RA expression is associated with the development of Crohn's disease ( 25 ) and rs61839660-T was previously shown to downregulate IL2RA expression by reducing affinity for the MEF2 factors ( 26 ). It is known that BRD4 can recruit P-TEFb to transcriptionally active promoters, and overexpression of P-TEFb stimulates MEF2-dependent transcription ( 27 ).…”

Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

“…3 h). Downregulation of some key CD-associated genes, notably CXCL9 [ 25 ], CEACAM1 [ 26 ], and JAK2 [ 27 , 28 ], was apparent among SP140 -siRNA-treated unstimulated macrophages, and IL2RA [ 29 ] and TRIM69 [ 30 ] among SP140 -siRNA LPS-stimulated macrophages (Fig. 3 i).…”