Anti-TNF immunotherapy reduces CD8+ T cell-mediated antimicrobial activity against Mycobacterium tuberculosis in humans
Anti-TNF immunotherapy reduces CD8+ T cell-mediated antimicrobial activity against Mycobacterium tuberculosis in humans
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DOI：
10.1172/jci38482
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发表时间：
2009-05-01
影响因子：
15.9
通讯作者：
Stenger, Steffen
中科院分区：
文献类型：
--
作者：
Bruns, Heiko;Meinken, Christoph;Stenger, Steffen
在用抗TNF抗体治疗自身免疫性疾病期间，结核病的发病率增加。这是一个重要的临床并发症，但也提供了一个独特的模型来研究人类结核病的免疫机制。鉴于细胞介导的免疫在宿主防御结核分枝杆菌中的关键作用，我们假设抗TNF治疗损害T细胞定向的抗微生物活性。抗TNF治疗降低了淋巴细胞中穿孔素和颗粒溶素的表达，这是T细胞介导的对细胞内病原体的抗菌反应的两种组分。具体来说，M。结核反应性CD 8（+）CCR 7（-）CD 45 RA（+）效应记忆T细胞（T-EMRA细胞）表达最高水平的颗粒溶素，溶解M.结核，和感染的巨噬细胞，并介导抗细胞内M.结核此外，T-EMRA细胞表达细胞表面TNF并在体外结合抗TNF治疗剂英夫利西单抗，使其对补体介导的裂解敏感。抗TNF免疫治疗与CD 8（+）T-EMRA细胞数量减少和抗M.结核病，这可以通过添加CD 8（+）T-EMRA细胞来挽救。这些结果表明，抗TNF治疗触发了具有抗M.结核病，提供洞察机制，其中关键效应T细胞亚群有助于宿主防御结核病。
The incidence of tuberculosis is increased during treatment of autoimmune diseases with anti-TNF antibodies. This is a significant clinical complication, but also provides a unique model to study immune mechanisms in human tuberculosis. Given the key role for cell-mediated immunity in host defense against Mycobacterium tuberculosis, we hypothesized that anti-TNF treatment impairs T cell-directed antimicrobial activity. Anti-TNF therapy reduced the expression in lymphocytes of perforin and granulysin, 2 components of the T cell-mediated antimicrobial response to intracellular pathogens. Specifically, M. tuberculosis-reactive CD8(+)CCR7(-)CD45RA(+) effector memory T cells (T-EMRA cells) expressed the highest levels of granulysin, lysed M. tuberculosis, and infected macrophages and mediated an antimicrobial activity against intracellular M. tuberculosis. Furthermore, T-EMRA cells expressed cell surface TNF and bound the anti-TNF therapeutic infliximab in vitro, making them susceptible to complement-mediated lysis. Immune therapy with anti-TNF was associated with reduced numbers of CD8(+) T-EMRA cells and decreased antimicrobial activity against M. tuberculosis, which could be rescued by the addition of CD8(+) T-EMRA cells. These results suggest that anti-TNF therapy triggers a reduction of CD8(+) T-EMRA cells with antimicrobial activity against M. tuberculosis, providing insight into the mechanism whereby key effector T cell subsets contribute to host defense against tuberculosis.