Phillips Bonnie L, Gautam Uma S, Bucsan Allison N, Foreman Taylor W, Golden Nadia A, Niu Tianhua, Kaushal Deepak, Mehra Smriti
Tulane National Primate Research Center, Covington, Louisiana, United States of America.
Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
PLoS One. 2017 Sep 7;12(9):e0180413. doi: 10.1371/journal.pone.0180413. eCollection 2017.
CD4+ T-cell mediated Th1 immune responses are critical for immunity to TB. The immunomodulatory protein, lymphocyte activation gene-3 (LAG-3) decreases Th1-type immune responses in T-cells. LAG-3 expression is significantly induced in the lungs of macaques with active TB and correlates with increased bacterial burden. Overproduction of LAG-3 can greatly diminish responses and could lead to uncontrolled Mtb replication. To assess the effect of LAG-3 on the progression of Mtb infection, we developed a co-culture system wherein blood-derived macrophages are infected with Mtb and supplemented with macaque blood or lung derived CD4+ T-cells. Silencing LAG-3 signaling in macaque lung CD4+ T-cells enhanced killing of Mtb in co-cultures, accompanied by reduced mitochondrial electron transport and increased IFN-γ expression. Thus, LAG-3 may modulate adaptive immunity to Mtb infection by interfering with the mitochondrial apoptosis pathway. Better understanding this pathway could allow us to circumvent immune features that promote disease.
CD4 + T细胞介导的Th1免疫反应对结核病免疫至关重要。免疫调节蛋白淋巴细胞激活基因-3（LAG-3）可降低T细胞中的Th1型免疫反应。在患有活动性结核病的猕猴肺部，LAG-3表达显著上调，且与细菌负荷增加相关。LAG-3的过度产生会大大削弱反应，并可能导致结核分枝杆菌不受控制地复制。为了评估LAG-3对结核分枝杆菌感染进程的影响，我们建立了一种共培养系统，其中用结核分枝杆菌感染源自血液的巨噬细胞，并补充猕猴血液或肺源性CD4 + T细胞。沉默猕猴肺CD4 + T细胞中的LAG-3信号可增强共培养物中结核分枝杆菌的杀伤作用，同时伴有线粒体电子传递减少和IFN-γ表达增加。因此，LAG-3可能通过干扰线粒体凋亡途径来调节对结核分枝杆菌感染的适应性免疫。更好地了解这一途径可以使我们规避促进疾病的免疫特征。
