Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL 60612.
J Immunol. 2014 Mar 1;192(5):2120-32. doi: 10.4049/jimmunol.1301373. Epub 2014 Jan 31.
The possibility that CD4(+) T cells can act as "innate-like" cells to contain very early Mycobacterium tuberculosis dissemination and function as master helpers to sustain multiple effector functions of CD8(+) T cells and CD3(-) lymphocytes during development of adaptive immunity against primary tuberculosis (TB) has not been demonstrated. We showed that pulmonary M. tuberculosis infection of CD4-depleted macaques surprisingly led to very early extrapulmonary M. tuberculosis dissemination, whereas CD4 deficiency clearly resulted in rapid TB progression. CD4 depletion during M. tuberculosis infection revealed the ability of CD8(+) T cells to compensate and rapidly differentiate to Th17-like/Th1-like and cytotoxic-like effectors, but these effector functions were subsequently unsustainable due to CD4 deficiency. Whereas CD3(-) non-T lymphocytes in the presence of CD4(+) T cells developed predominant Th22-like and NK-like (perforin production) responses to M. tuberculosis infection, CD4 depletion abrogated these Th22-/NK-like effector functions and favored IL-17 production by CD3(-) lymphocytes. CD4-depleted macaques exhibited no or few pulmonary T effector cells constitutively producing IFN-γ, TNF-α, IL-17, IL-22, and perforin at the endpoint of more severe TB, but they presented pulmonary IL-4(+) T effectors. TB granulomas in CD4-depleted macaques contained fewer IL-22(+) and perforin(+) cells despite the presence of IL-17(+) and IL-4(+) cells. These results implicate a previously unknown innate-like ability of CD4(+) T cells to contain extrapulmonary M. tuberculosis dissemination at very early stage. Data also suggest that CD4(+) T cells are required to sustain multiple effector functions of CD8(+) T cells and CD3(-) lymphocytes and to prevent rapid TB progression during M. tuberculosis infection of nonhuman primates.
CD4(+) T 细胞是否可以作为“先天样”细胞来控制早期结核分枝杆菌（Mycobacterium tuberculosis）的传播，并作为主辅助细胞来维持 CD8(+) T 细胞和 CD3(-) 淋巴细胞的多种效应功能，从而在原发性肺结核（TB）的适应性免疫发展过程中发挥作用，这一点尚未得到证实。我们发现，在 CD4 耗竭的猕猴中，肺部结核分枝杆菌感染竟然导致了非常早期的肺外结核分枝杆菌传播，而 CD4 缺陷明显导致了 TB 的快速进展。在结核分枝杆菌感染期间耗竭 CD4 揭示了 CD8(+) T 细胞的代偿能力，并迅速分化为 Th17 样/Th1 样和细胞毒性样效应器，但由于 CD4 缺陷，这些效应功能随后无法持续。虽然在存在 CD4(+) T 细胞的情况下，CD3(-) 非 T 淋巴细胞对结核分枝杆菌感染发展出主要的 Th22 样和 NK 样（穿孔素产生）反应，但 CD4 耗竭会阻断这些 Th22/NK 样效应功能，并有利于 CD3(-) 淋巴细胞产生 IL-17。CD4 耗竭的猕猴在更严重的 TB 终点时，没有或很少有肺 T 效应细胞持续产生 IFN-γ、TNF-α、IL-17、IL-22 和穿孔素，但它们表现出肺 IL-4(+) T 效应器。尽管存在 IL-17(+) 和 IL-4(+) 细胞，但 CD4 耗竭的猕猴中的结核肉芽肿含有较少的 IL-22(+) 和穿孔素(+)细胞。这些结果表明，CD4(+) T 细胞具有以前未知的先天样能力，可以在非常早期阶段控制肺外结核分枝杆菌的传播。数据还表明，在非人类灵长类动物的结核分枝杆菌感染过程中，CD4(+) T 细胞需要维持 CD8(+) T 细胞和 CD3(-) 淋巴细胞的多种效应功能，并防止 TB 的快速进展。
