Use of the Human Granulysin Transgenic Mice To Evaluate the Role of Granulysin Expression by CD8 T Cells in Immunity To Mycobacterium tuberculosis.
Use of the Human Granulysin Transgenic Mice To Evaluate the Role of Granulysin Expression by CD8 T Cells in Immunity To Mycobacterium tuberculosis.
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人类 NK 和 CD8 T 细胞的细胞毒性颗粒含有效应分子颗粒溶素。尽管体外研究表明颗粒溶素对结核分枝杆菌具有杀菌作用，并且人类 CD8 T 细胞通过颗粒胞吐作用限制细胞内结核分枝杆菌，但颗粒溶素在细胞介导的抗感染免疫中的作用尚不完全清楚，部分原因是小鼠中缺乏颗粒溶素基因直向同源物。在人类调节 DNA 序列的控制下表达人类颗粒溶素 (GNLY-Tg) 的转基因小鼠允许在体内研究颗粒溶素。我们评估了小鼠 CD8 T 细胞的颗粒溶素表达是否增强了其对结核分枝杆菌感染的控制。 GNLY-Tg 小鼠并不能比非 Tg 对照小鼠更好地控制肺部结核分枝杆菌感染，并且纯化的 GNLY-Tg 和非 Tg CD8 T 细胞具有相似的向 T 细胞缺陷小鼠转移保护的能力。来自感染对照和 GNLY 转基因小鼠的肺 CD8 T 细胞在体外同样控制巨噬细胞中细胞内结核分枝杆菌的生长。重要的是，在 GNLY-Tg 小鼠感染结核分枝杆菌后，在 NK 细胞中检测到颗粒溶素，但在 CD8 T 细胞中未检测到。只有经过长时间的体外刺激后，才能在抗原特异性 CD8 T 细胞中检测到颗粒溶素的表达。 GNLY-Tg 小鼠是一个不完善的模型，无法确定 CD8 T 细胞表达的颗粒溶素是否增强对结核分枝杆菌的免疫力。需要更好的表达颗粒溶素的模型来探索这种抗菌效应分子在体内的作用。
The cytotoxic granules of human NK and CD8 T cells contain the effector molecule granulysin. Although in vitro studies indicate that granulysin is bactericidal to Mycobacterium tuberculosis and human CD8 T cells restrict intracellular M. tuberculosis by granule exocytosis, the role of granulysin in cell-mediated immunity against infection is incompletely understood, in part because a granulysin gene ortholog is absent in mice. Transgenic mice that express human granulysin (GNLY-Tg) under the control of human regulatory DNA sequences permit the study of granulysin in vivo. We assessed whether granulysin expression by murine CD8 T cells enhances their control of M. tuberculosis infection. GNLY-Tg mice did not control pulmonary M. tuberculosis infection better than non-Tg control mice, and purified GNLY-Tg and non-Tg CD8 T cells had a similar ability to transfer protection to T cell deficient mice. Lung CD8 T cells from infected control and GNLY-transgenic mice similarly controlled intracellular M. tuberculosis growth in macrophages in vitro. Importantly, after M. tuberculosis infection of GNLY-Tg mice, granulysin was detected in NK cells but not in CD8 T cells. Only after prolonged in vitro stimulation could granulysin expression be detected in antigen-specific CD8 T cells. GNLY-Tg mice are an imperfect model to determine whether granulysin expression by CD8 T cells enhances immunity against M. tuberculosis. Better models expressing granulysin are needed to explore the role of this antimicrobial effector molecule in vivo.
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