期刊
JOURNAL OF CROHNS & COLITIS
卷 15, 期 12, 页码 2054-2065出版社
OXFORD UNIV PRESS
DOI: 10.1093/ecco-jcc/jjab103
关键词
Crohn's disease; T cells; TREGs; CD25; IL-2; basiliximab
资金
- Medical Research Council [MR/R001413/1]
- Guts UK/forCrohns Development grant [DGC2019_02]
- National Institute for Health [NIHR] Biomedical Research Centres at Guy's & St Thomas' NHS Foundation Trust and King's College London
- Cambridge University Hospital NHS Foundation Trust
- University of Cambridge
- MRC [MR/R001413/1] Funding Source: UKRI
The study reveals that IBD patients carrying the rs61839660 SNP show an enhanced T-eff immune phenotype with increased pro-inflammatory cytokine expression in response to IL-2 stimulation, while individuals with the TT genotype may exhibit a more active gut homing phenotype and reduced T cell clonal capacity.
Background and Aims: Differential responsiveness to interleukin [IL]-2 between effector CD4(+) T cells [T-eff] and regulatory T cells [T-reg] 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: T-eff and T-reg were isolated from individuals homozygous [TT], heterozygous [CT], or wildtype [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. T-eff 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 T-eff in response to IL-2 stimulation in vitro. T-eff 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 T-reg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype.
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