Laochumroonvorapong P, Wang J, Liu C C, Ye W, Moreira A L, Elkon K B, Freedman V H, Kaplan G
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021, USA.
Infect Immun. 1997 Jan;65(1):127-32. doi: 10.1128/iai.65.1.127-132.1997.
Host defense against mycobacterial infection requires the participation of monocytes and T cells. Both CD4+ and CD8+ T cells have been shown to be important in resistance to mycobacterial infection in vivo. The main contribution of CD4+ T cells to the protective antituberculosis response involves the production of Th1-type cytokines, including interleukin-2 (IL-2) and gamma interferon (IFN-gamma). CD8+ T cells have been considered to be responsible primarily for cytotoxicity mediated by toxic molecules, including perforin. CD8+ T cells may also elaborate Th1-type cytokines, such as IFN-gamma, in response to the infection. To elucidate the contribution of perforin-mediated target cell death to the control of mycobacterial infection in vivo, mice with a disruption in the perforin gene (P-/-) were infected with Mycobacterium bovis BCG or M. tuberculosis Erdman for 5 and 13 weeks, respectively. At 1, 3, 5, and 13 weeks postinfection, the number of viable mycobacteria in the lungs, spleens, and livers of mice were determined by CFU assay. The infected tissues were examined histologically, and cytokine mRNA levels in the spleens of these mice were determined. Similar studies were carried out in Fas receptor-defective (CBA/lpr(cg)) mice to evaluate the contribution of this alternative cytotoxic pathway to the control of mycobacterial infection. The absence of either perforin gene function or Fas receptor gene function did not modify the course of experimental mycobacterial infection in these mice. In addition, both P-/- and Fas receptor-defective mice appeared to have a compensatory activation of cytokine genes, even in the absence of the experimental infection. P-/- mice had a mean 3.4- to 5-fold increase in mRNA levels for IL-10, IL-12p35, IL-6, and IFN-gamma. Similarly, Fas receptor-defective mice had a mean 3- to 3.6-fold increase in mRNA levels for IFN-gamma, IL-12p35, and IL-10. Our results indicate that both perforin-mediated cytotoxicity and Fas-mediated cytotoxicity do not appear to be necessary for the early control of mycobacterial infection in vivo.
机体对分枝杆菌感染的防御需要单核细胞和T细胞的参与。CD4⁺和CD8⁺ T细胞在体内抵抗分枝杆菌感染中均发挥重要作用。CD4⁺ T细胞对保护性抗结核反应的主要贡献涉及Th1型细胞因子的产生，包括白细胞介素-2（IL-2）和γ干扰素（IFN-γ）。CD8⁺ T细胞主要被认为负责由包括穿孔素在内的毒性分子介导的细胞毒性作用。CD8⁺ T细胞也可能在感染时产生Th1型细胞因子，如IFN-γ。为了阐明穿孔素介导的靶细胞死亡在体内控制分枝杆菌感染中的作用，分别用牛分枝杆菌卡介苗或结核分枝杆菌埃尔德曼菌株感染穿孔素基因缺失（P⁻/⁻）的小鼠5周和13周。在感染后1、3、5和13周，通过菌落形成单位（CFU）测定法确定小鼠肺、脾和肝中活分枝杆菌的数量。对感染组织进行组织学检查，并测定这些小鼠脾脏中细胞因子mRNA水平。在Fas受体缺陷（CBA/lpr（cg））小鼠中进行了类似研究，以评估这种替代细胞毒性途径在控制分枝杆菌感染中的作用。穿孔素基因功能或Fas受体基因功能的缺失均未改变这些小鼠实验性分枝杆菌感染的进程。此外，即使在没有实验性感染的情况下，P⁻/⁻小鼠和Fas受体缺陷小鼠似乎也有细胞因子基因的代偿性激活。P⁻/⁻小鼠中IL-10、IL-12p35、IL-6和IFN-γ的mRNA水平平均增加3.4至5倍。同样，Fas受体缺陷小鼠中IFN-γ、IL-12p35和IL-10的mRNA水平平均增加3至3.6倍。我们的结果表明，穿孔素介导的细胞毒性和Fas介导的细胞毒性在体内对分枝杆菌感染的早期控制似乎并非必需。
