FliC-specific CD4+ T cell responses are restricted by bacterial regulation of antigen expression
FliC-specific CD4+ T cell responses are restricted by bacterial regulation of antigen expression
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DOI：
10.4049/jimmunol.174.12.7929
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发表时间：
2005-06-15
影响因子：
4.4
通讯作者：
Cookson, BT
中科院分区：
文献类型：
--
作者：
Cummings, LA;Barrett, SLR;Cookson, BT
鼠伤寒沙门氏菌是一种兼性的细胞内病原体，它调节毒力因子的表达，以应对感染过程中遇到的不同环境。我们测试了这样的假设，即在沙门氏菌感染期间从细胞外环境到细胞内环境的转变触发了抗原表达的变化，从而对宿主T细胞反应施加了时间和空间上的限制。从沙门氏菌免疫小鼠中恢复的CD4+T细胞使用从细菌中提取的抗原在体外繁殖，这些细菌生长在旨在模拟体内细胞外或细胞内环境的条件下。胞外相细菌支持对鞭毛亚单位蛋白flc的主要T细胞反应，而胞内相细菌不能支持从已知包含对该抗原有反应的T细胞的群体中扩增出flic特异性T细胞。这一结果归因于细菌对flc表达的调节：在感染小鼠的脾中生长的细菌的转录和蛋白质水平受到抑制。此外，沙门氏菌感染的脾细胞只有在细胞内Flc表达被人为上调的情况下，才能在体外直接刺激Flc特异性T细胞克隆。虽然在体内存在免疫T细胞和感染的APC的显微解剖分离，但我们证明细胞内沙门氏菌可以将flc的表达抑制在T细胞激活阈值以下。这可能为全身部位的细胞内沙门氏菌提供了一种机制，以避免在感染早期被肠道部位的Ag特异性T细胞检测到。
Salmonella typhimurium, a facultatively intracellular pathogen, regulates expression of virulence factors in response to distinct environments encountered during the course of infection. We tested the hypothesis that the transition from extra- to intracellular environments during Salmonella infection triggers changes in Ag expression that impose both temporal and spatial limitations on the host T cell response. CD4+ T cells recovered from Salmonella immune mice were propagated in vitro using Ag derived from bacteria grown in conditions designed to emulate extra- or intracellular environments in vivo. Extracellular phase bacteria supported a dominant T cell response to the flagellar subunit protein FliC, whereas intracellular phase bacteria were unable to support expansion of FliC-specific T cells from populations known to contain T cells with reactivity to this Ag. This result was attributed to bacterial regulation of FliC expression: transcription and protein levels were repressed in bacteria growing in the spleens of infected mice. Furthermore, Salmonella-infected splenocytes taken directly ex vivo stimulated FliC-specific T cell clones only when intracellular FliC expression was artificially up-regulated. Although it has been suggested that a microanatomical separation of immune T cells and infected APC exists in vivo, we demonstrate that intracellular Salmonella can repress FliC expression below the T cell activation threshold. This potentially provides a mechanism for intracellular Salmonella at systemic sites to avoid detection by Ag-specific T cells primed at intestinal sites early in infection.