Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Immunity. 2009 Dec 18;31(6):974-85. doi: 10.1016/j.immuni.2009.10.007.
Immunity to Mycobacterium tuberculosis in humans and in mice requires interferon gamma (IFN-gamma). Whereas IFN-gamma has been studied extensively for its effects on macrophages in tuberculosis, we determined that protective immunity to tuberculosis also requires IFN-gamma-responsive nonhematopoietic cells. Bone marrow chimeric mice with IFN-gamma-unresponsive lung epithelial and endothelial cells exhibited earlier mortality and higher bacterial burdens than control mice, underexpressed indoleamine-2,3-dioxygenase (Ido1) in lung endothelium and epithelium, and overexpressed interleukin-17 (IL-17) with massive neutrophilic inflammation in the lungs. We also found that the products of IDO catabolism of tryptophan selectively inhibit IL-17 production by Th17 cells, by inhibiting the action of IL-23. These results reveal a previously unsuspected role for IFN-gamma responsiveness in nonhematopoietic cells in regulation of immunity to M. tuberculosis and illustrate the role of IDO in the inhibition of Th17 cell responses.
人类和小鼠对结核分枝杆菌的免疫需要干扰素 γ（IFN-γ）。虽然 IFN-γ 已被广泛研究其在结核病中对巨噬细胞的作用，但我们确定对结核病的保护性免疫还需要 IFN-γ 反应性非造血细胞。IFN-γ 无反应性肺上皮和内皮细胞的骨髓嵌合小鼠比对照小鼠更早死亡，肺部细菌负荷更高，肺内皮细胞和上皮细胞中吲哚胺 2,3-双加氧酶（Ido1）表达下调，白细胞介素-17（IL-17）过度表达，肺部发生大量中性粒细胞炎症。我们还发现色氨酸分解代谢产物 IDO 的产物通过抑制 IL-23 的作用选择性地抑制 Th17 细胞产生 IL-17。这些结果揭示了 IFN-γ 反应性非造血细胞在调节结核分枝杆菌免疫中的先前未被怀疑的作用，并说明了 IDO 在抑制 Th17 细胞反应中的作用。
