Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: Insights into T-cell unresponsiveness in leprosy
Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: Insights into T-cell unresponsiveness in leprosy
复制标题
DOI：
10.1016/j.molimm.2009.11.009
复制
发表时间：
2010-02-01
影响因子：
3.6
通讯作者：
Joshi, Beenu
中科院分区：
文献类型：
--
作者：
Dagur, Pradeep K.;Sharma, Bhawna;Joshi, Beenu
本研究探讨了麻风分枝杆菌(M)抗原在TCR和TCR/CD28诱导的T细胞活化信号中的作用，并进一步将这些早期生化事件与晚期麻风患者普遍存在的T细胞无能联系起来。观察到，全细胞赖氨酸(WCL)和麻风可溶性部分(MLSA)不仅通过减少钙通道的开放来抑制TCR、thapsigargin和离子霉素诱导的钙离子流，对TCR和TCR/CD28诱导的下游信号的研究表明，M抗原抑制ERK1/2和p38MAPK的磷酸化，从而改变末端信号事件，如NFAT与IL-2启动子的结合减少和IL-2基因的转录。活化标志物(CD25和CD69)的表达减少此外，麻风杆菌组分显著抑制健康人IL-2的分泌和T细胞的生成。结果表明，麻风杆菌干扰TCR/CD28诱导的上游和下游信号事件，导致IL-2产生减少，从而抑制T细胞增殖，这可能是导致T细胞无应答导致免疫抑制阶段，从而导致疾病进展的原因。(C)2009爱思唯尔有限公司保留所有权利。
Present study investigates the role of Mycobacterium leprae (M leprae) antigens on TCR- and TCR/CD28-induced signalling leading to T-cell activation and further correlates these early biochemical events with T-cell anergy, as prevailed in advanced stages of leprosy We observed that both whole cell lystae (WCL) and Soluble fraction of M leprae sonicate (MLSA) not only inhibited TCR, thapsigargin and ionomycin induced calcium fluxes by diminishing the opening of calcium channels, but also TCR- or TCR/CD28-induced proximal signalling events like phosphorylation of Zap-70 and protein kinase-C (PKC) activity Study of TCR- and TCR/CD28-induced downstream signals revealed that M leprae antigens curtail phosphorylation of both Erk1/2 and p38MAPK, consequently altering terminal signalling events like reduced binding of NFAT on IL-2 promoter and transcription of IL-2 gene. diminished expression of activation markers (CD25 and CD69) Furthermore, M. leprae fractions significantly inhibited IL-2 secretion and T-cell blastogenesis in healthy individuals Altogether results suggest that M leprae interferes wit TCR/CD28-induced upstream as well as downstream signalling events resulting in reduced IL-2 production and thus inhibition in T-cell proliferation, which might be responsible for T-cell unresponsiveness leading to stage Of immunosuppression and consequently, for the progression of disease. (C) 2009 Elsevier Ltd All rights reserved.