TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG
TLR2 and TLR4 serve distinct roles in the host immune response against Mycobacterium bovis BCG
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DOI：
10.1189/jlb.0103026
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发表时间：
2003-08-01
影响因子：
5.5
通讯作者：
Fenton, MJ
中科院分区：
文献类型：
--
作者：
Heldwein, KA;Liang, MD;Fenton, MJ
Toll样受体(TLR)蛋白介导微生物和微生物产物对细胞的激活。用非致病性牛分枝杆菌卡介苗(BCG)感染野生型和TLR基因缺陷小鼠，探讨TLR蛋白在宿主抗分枝杆菌免疫应答中的作用。卡介苗攻击2周后，野生型和TLR4(-/-)小鼠肺内细菌稀少，而感染TLR2(-/-)小鼠肺内细菌载量增加10倍。卡介苗体外攻击可强烈诱导野生型和TLR4(-/-)小鼠巨噬细胞分泌促炎细胞因子，但不能诱导TLR2(-/-)小鼠巨噬细胞分泌促炎细胞因子。相反，三个品系的小鼠巨噬细胞的细胞内摄取、细胞内细菌生长以及干扰素-γ对细胞内细菌生长的抑制作用都是相似的，这表明TLR2(-/-)小鼠肺内卡介苗的生长是适应性免疫缺陷的结果。感染野生型和TLR4(-/-)小鼠的脾细胞经抗原刺激后，在体外可诱导T细胞增殖，而TLR2(-/-)小鼠的T细胞不能增殖。出乎意料的是，与对照T细胞相比，两个TLR缺陷小鼠品系的激活的CD4(+)T细胞在体外分泌的干扰素-γ很少。只有当小鼠感染较高数量的卡介苗时，才能观察到TLR4在体内控制细菌生长和干扰素-γ产生的作用。因此，TLR2和TLR4似乎调节针对卡介苗的宿主免疫反应的不同方面。
Toll-like receptor (TLR) proteins mediate cellular activation by microbes and microbial products. To delineate the role of TLR proteins in the development of host immune responses against mycobacteria, wild-type and TLR-deficient mice were infected with nonpathogenic Mycobacterium bovis bacillus Calmette-Guerin (BCG). Two weeks after intraperitoneal challenge with BCG, few bacilli were present in the lungs of wild-type and TLR4(-/-) mice, whereas bacterial loads were tenfold higher in the lungs of infected TLR2(-/-) mice. BCG challenge in vitro strongly induced proinflammatory cytokine secretion by macrophages from wild-type and TLR4(-/-) mice but not by TLR2(-/-) macrophages. In contrast, intracellular uptake, intracellular bacterial growth, and suppression of intracellular bacterial growth in vitro by interferon-gamma (IFN-gamma) were similar in macrophages from all three mouse strains, suggesting that BCG growth in the lungs of TLR2(-/-) mice was a consequence of defective adaptive immunity. Antigenic stimulation of splenocytes from infected wild-type and TLR4(-/-) mice induced T cell proliferation in vitro, whereas T cells from TLR2(-/-) mice failed to proliferate. Unexpectedly, activated CD4(+) T cells from both TLR-deficient mouse strains secreted little IFN-gamma in vitro compared with control T cells. A role for TLR4 in the control of bacterial growth and IFN-gamma production in vivo was observed only when mice were infected with higher numbers of BCG. Thus, TLR2 and TLR4 appear to regulate distinct aspects of the host immune response against BCG.