Cowley Siobhán C, Elkins Karen L
Laboratory of Mycobacterial Diseases and Cellular Immunology, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research/Food and Drug Administration, Rockville, MD 20852, USA.
J Immunol. 2003 Nov 1;171(9):4689-99. doi: 10.4049/jimmunol.171.9.4689.
Although IFN-gamma is necessary for survival of Mycobacterium tuberculosis infection in people and animal models, it may not be sufficient to clear the infection, and IFN-gamma is not a reliable correlate of protection. To determine whether IFN-gamma-independent mechanisms of immunity exist, we developed a murine ex vivo culture system that directly evaluates the ability of splenic or lung lymphocytes to control the growth of M. tuberculosis within infected macrophages, and that models in vivo immunity to tuberculosis. Surprisingly, CD4(+) T cells controlled >90% of intracellular M. tuberculosis growth in the complete absence of IFN-gamma stimulation of macrophages, via a NO-dependent mechanism. Furthermore, bacillus Calmette-Guerin-vaccinated IFN-gamma-deficient mice exhibited significant protection against M. tuberculosis challenge that was lost upon depletion of CD4(+) T cells. These findings demonstrate that CD4(+) T cells possess IFN-gamma-independent mechanisms that can limit the growth of an intracellular pathogen and are dominant in secondary responses to M. tuberculosis.
虽然干扰素-γ对于人类和动物模型中结核分枝杆菌感染的存活是必需的，但它可能不足以清除感染，且干扰素-γ并非可靠的保护性相关指标。为了确定是否存在不依赖干扰素-γ的免疫机制，我们开发了一种小鼠离体培养系统，该系统可直接评估脾淋巴细胞或肺淋巴细胞控制感染巨噬细胞内结核分枝杆菌生长的能力，并模拟体内对结核病的免疫。令人惊讶的是，在巨噬细胞完全缺乏干扰素-γ刺激的情况下，CD4(+) T细胞通过一种依赖一氧化氮的机制控制了>90%的细胞内结核分枝杆菌生长。此外，接种卡介苗的干扰素-γ缺陷小鼠对结核分枝杆菌攻击表现出显著的保护作用，而这种保护作用在CD4(+) T细胞耗竭后消失。这些发现表明，CD4(+) T细胞具有不依赖干扰素-γ的机制，可限制细胞内病原体的生长，并且在对结核分枝杆菌的二次应答中占主导地位。
