South African Tuberculosis Vaccine Initiative and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.
J Immunol. 2011 Sep 1;187(5):2222-32. doi: 10.4049/jimmunol.1101122. Epub 2011 Jul 20.
High Ag load in chronic viral infections has been associated with impairment of Ag-specific T cell responses; however, the relationship between Ag load in chronic Mycobacterium tuberculosis infection and functional capacity of M. tuberculosis-specific T cells in humans is not clear. We compared M. tuberculosis-specific T cell-associated cytokine production and proliferative capacity in peripheral blood from adults with progressively higher mycobacterial loads-that is, persons with latent M. tuberculosis infection (LTBI), with smear-negative pulmonary tuberculosis (TB), and smear-positive TB. Patients with smear-positive TB had decreased polyfunctional IFN-γ(+)IL-2(+)TNF-α(+) and IL-2-producing specific CD4 T cells and increased TNF-α single-positive cells, when compared with smear-negative TB and LTBI. TB patients also had increased frequencies of M. tuberculosis-specific CD8 T cells, compared with LTBI. M. tuberculosis-specific CD4 and CD8 T cell proliferative capacity was profoundly impaired in individuals with smear-positive TB, and correlated positively with ex vivo IFN-γ(+)IL-2(+)TNF-α(+) CD4 T cells, and inversely with TNF-α single-positive CD4 T cells. During 6 mo of anti-TB treatment, specific IFN-γ(+)IL-2(+)TNF-α(+) CD4 and CD8 T cells increased, whereas TNF-α and IFN-γ single-positive T cells decreased. These results suggest progressive impairment of M. tuberculosis-specific T cell responses with increasing mycobacterial load and recovery of responses during therapy. Furthermore, these data provide a link between specific cytokine-producing subsets and functional capacity of M. tuberculosis-specific T cells, and between the presence of specific CD8 T cells ex vivo and active TB disease. These data have potentially significant applications for the diagnosis of TB and for the identification of T cell correlates of TB disease progression.
慢性病毒感染中高抗原负荷与抗原特异性 T 细胞应答受损有关；然而，慢性结核分枝杆菌感染中抗原负荷与结核分枝杆菌特异性 T 细胞功能能力之间的关系尚不清楚。我们比较了来自具有逐渐升高分枝杆菌负荷的成年人的结核分枝杆菌特异性 T 细胞相关细胞因子产生和增殖能力，即潜伏性结核分枝杆菌感染（LTBI）、痰涂片阴性肺结核（TB）和痰涂片阳性 TB 患者。与痰涂片阴性 TB 和 LTBI 相比，痰涂片阳性 TB 患者的多功能 IFN-γ（+）IL-2（+）TNF-α（+）和产生 IL-2 的特异性 CD4 T 细胞减少，TNF-α 单阳性细胞增加。与 LTBI 相比，TB 患者也有更多的结核分枝杆菌特异性 CD8 T 细胞。与 LTBI 相比，痰涂片阳性 TB 个体的结核分枝杆菌特异性 CD4 和 CD8 T 细胞增殖能力严重受损，与体外 IFN-γ（+）IL-2（+）TNF-α（+）CD4 T 细胞呈正相关，与 TNF-α 单阳性 CD4 T 细胞呈负相关。在 6 个月的抗结核治疗期间，特异性 IFN-γ（+）IL-2（+）TNF-α（+）CD4 和 CD8 T 细胞增加，而 TNF-α 和 IFN-γ 单阳性 T 细胞减少。这些结果表明，随着分枝杆菌负荷的增加，结核分枝杆菌特异性 T 细胞应答逐渐受损，而在治疗过程中应答得到恢复。此外，这些数据提供了结核分枝杆菌特异性细胞因子产生亚群与结核分枝杆菌特异性 T 细胞功能能力之间以及体外特异性 CD8 T 细胞与活动性结核病之间的联系。这些数据对于结核病的诊断和结核疾病进展的 T 细胞相关性标志物的鉴定具有潜在的重要意义。
