A Crohn's Disease-associated IL2RA Enhancer Variant Determines the Balance of T Cell Immunity by Regulating Responsiveness to IL-2 Signalling.
A Crohn's Disease-associated IL2RA Enhancer Variant Determines the Balance of T Cell Immunity by Regulating Responsiveness to IL-2 Signalling.
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克罗恩疾病相关的IL2RA增强子变体通过调节对IL-2信号的反应性来决定T细胞免疫的平衡。
DOI：
10.1093/ecco-jcc/jjab103
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发表时间：
2021-12-18
期刊：
影响因子：
--
通讯作者：
Lord GM
中科院分区：
文献类型：
--
作者：
Goldberg R;Clough JN;Roberts LB;Sanchez J;Kordasti S;Petrov N;Hertweck A;Lorenc A;Jackson I;Tasker S;Appios A;Omer O;Parkes M;Prescott N;Jenner RG;Irving PM;Lord GM
效应T细胞和调节性T细胞对IL-2的不同反应性是免疫调节的一个基本机制。位于IL2RA[CD25]内的单核苷酸多态[SNP]rs61839660与克罗恩病[CD]的发生有关。我们试图确定携带该SNP的IBD患者的T细胞免疫表型。从rs61839660的纯合子[TT]、杂合子[CT]或野生型[CC]个体中分离到Teff和Treg，并用于表型分析[流式细胞术、细胞计数法飞行时间]功能分析或T细胞受体[TCR]测序。在IL-2、IL-7和针对CD25的单抗巴利昔单抗存在的情况下，检测信号转导和转录激活子5[STAT5]的磷酸化。用逆转录定量聚合酶链式反应检测IL-2和/或TCR刺激后TEFF促炎细胞因子的表达水平。微小T等位基因的存在增强了CD25的表达，导致STAT5磷酸化和促炎细胞因子转录表达增加，以响应IL-2的刺激。TT个体的苔藓表现出更活跃的肠道归巢表型。TCR测序分析表明，TT患者的克隆能力可能降低，以获得最佳的调节性T细胞反应。Rs61839660通过调节CD25的表达来调节T细胞对IL-2信号的反应性。由于低剂量的IL-2正在作为CD的选择性Treg调节剂进行试验，这些发现突显了这种基因型患者的潜在不良反应。
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. 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. 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. 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.
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CD127表达与FOXP3和人类CD4+ T Reg细胞的抑制功能成反比。
DOI：
10.1084/jem.20060772
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
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影响因子：
4.6
作者：
Kircher, B;Lätzer, K;Nachbaur, D
通讯作者：
Nachbaur, D
影响因子：
64.8
作者：
Simeonov DR;Gowen BG;Boontanrart M;Roth TL;Gagnon JD;Mumbach MR;Satpathy AT;Lee Y;Bray NL;Chan AY;Lituiev DS;Nguyen ML;Gate RE;Subramaniam M;Li Z;Woo JM;Mitros T;Ray GJ;Curie GL;Naddaf N;Chu JS;Ma H;Boyer E;Van Gool F;Huang H;Liu R;Tobin VR;Schumann K;Daly MJ;Farh KK;Ansel KM;Ye CJ;Greenleaf WJ;Anderson MS;Bluestone JA;Chang HY;Corn JE;Marson A
通讯作者：
Marson A
影响因子：
48
作者：
Diggins KE;Greenplate AR;Leelatian N;Wogsland CE;Irish JM
通讯作者：
Irish JM
影响因子：
56.9
作者：
Hori, S;Nomura, T;Sakaguchi, S
通讯作者：
Sakaguchi, S