Cross-reactive antigen is required to prevent erosion of established T cell memory and tumor immunity: A heterologous bacterial model of attrition
Cross-reactive antigen is required to prevent erosion of established T cell memory and tumor immunity: A heterologous bacterial model of attrition
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DOI：
10.4049/jimmunol.169.3.1197
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发表时间：
2002-08-01
影响因子：
4.4
通讯作者：
Sad, S
中科院分区：
文献类型：
--
作者：
Smith, DK;Dudani, R;Sad, S
T细胞记忆的诱导和维持对于细胞内病原体和肿瘤的控制至关重要。记忆T细胞似乎需要很少的“维持信号”，尽管这些研究通常是在没有竞争性免疫挑战的情况下进行的。相反，尽管在异源病毒模型中已经表征了CD 8（+）T细胞记忆的损耗，但细菌感染的情况并非如此。在这项研究中，我们证明了细胞内病原体单核细胞增生李斯特菌（LM）的免疫挑战后，与第二个细胞内的细菌，牛分枝杆菌（卡介苗，BCG）的T细胞反应的磨损。用LM或重组LM（表达OVA; LM-OVA）免疫的小鼠产生有效的T细胞记忆应答。这通过肽特异性CTL、IFN-γ产生和分泌WN-γ的T细胞对天然或重组LM Ag的频率来反映。然而，当LM感染的小鼠随后用BCG攻击时，LM特异性T细胞应答显著降低。这些减少直接归因于对CD 4（+）和CD 8（+）T细胞的影响，并且数据与LM特异性T细胞的损失一致，而不是无反应性。当用随后表达OVA的异源病原体（BCG）攻击LM-OVA免疫的小鼠时，Ag（OVA）特异性T细胞应答的减弱被阻止，证明记忆T细胞对Ag的依赖性。虽然LM特异性T细胞应答的减少并没有损害对随后LM再攻击的保护，但我们首次表明T细胞磨损可导致先前用LM-OVA免疫建立的Ag特异性抗肿瘤（B16.0VA）免疫的减少。
Induction and maintenance of T cell memory is critical for the control of intracellular pathogens and tumors. Memory T cells seem to require few "maintenance signals," though often such studies are done in the absence of competing immune challenges. Conversely, although attrition of CD8(+) T cell memory has been characterized in heterologous viral models, this is not the case for bacterial infections. In this study, we demonstrate attrition of T cell responses to the intracellular pathogen Listeria monocytogenes (LM) following an immune challenge with a second intracellular bacterium, Mycobacterium bovis (bacillus Calmette-Guerin, BCG). Mice immunized with either LM or recombinant LM (expressing OVA; LM-OVA), develop a potent T cell memory response. This is reflected by peptide-specific CTL, IFN-gamma production, and frequency of WN-gamma-secreting T cells to native or recombinant LM Ags. However, when the LM-infected mice are subsequently challenged with BCG, there is a marked reduction in the LM-specific T cell responses. These reductions are directly attributable to the effects on CD4(+) and CD8(+) T cells and the data are consistent with a loss of LM-specific T cells, not anergy. Attrition of the Ag (OVA)-specific T cell response is prevented when LM-OVA-immunized mice are challenged with a subsequent heterologous pathogen (BCG) expressing OVA, demonstrating memory T cell dependence on Ag. Although the reduction of the LM-specific T cell response did not impair protection against a subsequent LM rechallenge, for the first time, we show that T cell attrition can result in the reduction of Ag-specific antitumor (B16.0VA) immunity previously established with LM-OVA immunization.