Yee D, Rhinehart-Jones T R, Elkins K L
Laboratory of Enteric and Sexually Transmitted Diseases, Division of Bacterial Products, Center for Biologics Evaluation and Research, Rockville, MD 20852, USA.
J Immunol. 1996 Dec 1;157(11):5042-8.
Normal mice readily survive a sublethal intradermal (i.d.) infection with Francisella tularensis live vaccine strain (LVS), a model intracellular bacterium, and are strongly protected against subsequent lethal challenge. However, athymic nu/nu mice, which lack mature alphabeta TCR+ T lymphocytes, succumb to i.d. infection within 30 days. Here we characterize the alphabeta T cell subpopulations necessary for both resolution of i.d. infection and generation of optimal protective immunity to LVS. BALB/cByJ mice treated with anti-CD4 or anti-CD8 Abs before i.d. infection survived and cleared bacteria, and anti-CD4- or anti-CD8-treated immune mice survived a very strong i.p. challenge of 10,000 LD50s. Among mutant mice with targeted gene disruptions (knockouts), CD4-, beta2-microglobulin-deficient (which are also CD8-), and gammadelta TCR- mice all resolved a large sublethal i.d. infection. All CD4- and beta2-microglobulin-deficient mice readily survived subsequent lethal i.p. challenge of 10,000 LD50s, even in the absence of specific IgG Abs, as did most (86%) gammadelta TCR- mice. In contrast, alphabeta TCR- mice or alphabeta + gammadelta TCR- mice died about 35 days after i.d. infection. Depletion of gammadelta+ T cells from alphabeta TCR- mice had no effect on mean time to death from i.d. LVS infection. Therefore alphabeta TCR+ cells are required for protection, but either CD4+ or CD8+ T cells are individually sufficient to resolve a large sublethal i.d. LVS infection and to protect against a maximal secondary lethal challenge. These results emphasize the remarkable plasticity of the alphabeta T cell response in protective immunity to intracellular bacteria.
正常小鼠能够轻易在皮内（i.d.）感染致死剂量以下的土拉弗朗西斯菌活疫苗株（LVS，一种细胞内细菌模型）后存活，并能有效抵御随后的致死性攻击。然而，缺乏成熟αβTCR⁺T淋巴细胞的无胸腺裸鼠（nu/nu）在皮内感染后30天内会死亡。在此，我们对皮内感染的清除以及对LVS产生最佳保护性免疫所需的αβT细胞亚群进行了表征。在皮内感染前用抗CD4或抗CD8抗体处理的BALB/cByJ小鼠存活并清除了细菌，且经抗CD4或抗CD8处理的免疫小鼠在接受10,000个半数致死剂量（LD50）的腹腔强攻击后仍存活。在具有靶向基因破坏（基因敲除）的突变小鼠中，CD4⁻、β2微球蛋白缺陷型（其也为CD8⁻）和γδTCR⁻小鼠均能清除大量致死剂量以下的皮内感染。所有CD4⁻和β2微球蛋白缺陷型小鼠在接受10,000个LD50的腹腔致死性攻击后均能轻易存活，即使在没有特异性IgG抗体的情况下也是如此，大多数（86%）γδTCR⁻小鼠也是如此。相比之下，αβTCR⁻小鼠或αβ + γδTCR⁻小鼠在皮内感染后约35天死亡。从αβTCR⁻小鼠中耗尽γδ⁺T细胞对皮内LVS感染的平均死亡时间没有影响。因此，αβTCR⁺细胞是提供保护所必需的，但单独的CD4⁺或CD8⁺T细胞足以清除大量致死剂量以下的皮内LVS感染并抵御最大程度的二次致死性攻击。这些结果强调了αβT细胞反应在针对细胞内细菌的保护性免疫中的显著可塑性。
