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How MHC class II molecules promote memory CD8 T cell homeostasis

MHC II 类分子如何促进记忆 CD8 T 细胞稳态

基本信息

批准号：
23790549
负责人：
SETOGUCHI Ruka
金额：
$ 2.75万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23790549/
关键词：
免疫学的記憶免疫記憶

项目摘要

Memory CD8 T cells are long-lived antigen (Ag)-specific CD8 T cells which respond quickly, proliferate robustly, and exert effector functions faster than naive CD8 T cells upon reencounter with the specific Ags. Memory CD8 T cells are maintained at a stable size over a long period of time, but the mechanisms by which their population size is maintained remain elusive. It has been proposed that the maintenance of memory CD8 T cells depends on “CD4 T cell help”, based on the observation that CD8+ T cells which have been primed with Ags in wild-type (WT) mice survive poorly when transferred into MHCII-/- hosts as comparedto WT hosts. Our results clearly show that the impaired maintenance of memory CD8 T cells in MHCII-/- mice is not due to the absence of CD4+ helper T cells. This was shown by transferring Ag-primed CD8+ T cells into WT mice treated with the anti-CD4 GK1.5 mAb, or CD4-/- mice, or ThPOK mutant mice, all of which lack functional CD4+ helper T cells. We also found that MHCII molecules expressed by hematopoietic cells, not by non-hematopoietic cells, are required for memory CD8 T cell maintenance. The mRNA expression levels of IL-7 and IL-15, cytokines reported tobe important for memory CD8 T cell homeostasis, were comparable in the spleens of MHCII-/- and WT mice. We have not found the different expression levels of cytokines, chemokines, and growth factors in the serum of MHCII-/- and WT mice so far. However, microarray analysis of genes expressed by transferred CD8 T cells in MHCII-/- and WT mice displayed 77 different expression levels of genes. We are currently attemptingto uncover the function of these candidate genes in memory CD8 T cell maintenance.

记忆性CD8 T细胞是一种长寿命的抗原特异性CD8 T细胞，在再次遇到特异性Ags时，其反应迅速，增殖强劲，并且比初始CD8 T细胞更快地发挥效应功能。记忆性CD8 T细胞在很长一段时间内保持在一个稳定的大小，但其种群大小维持的机制仍然是难以捉摸的。研究发现，野生型（WT）小鼠携带Ags的CD8+ T细胞转移到MHCII-/-宿主后，与WT宿主相比，CD8+ T细胞的存活率较低，因此有人提出记忆性CD8 T细胞的维持依赖于“CD4 T细胞帮助”。我们的研究结果清楚地表明，MHCII-/-小鼠记忆性CD8 T细胞的维持受损不是由于缺乏CD4+辅助T细胞。这是通过将ag引发的CD8+ T细胞转移到抗CD4 GK1.5 mAb处理的WT小鼠，或CD4-/-小鼠，或ThPOK突变小鼠中来证明的，所有这些小鼠都缺乏功能性CD4+辅助T细胞。我们还发现MHCII分子由造血细胞表达，而不是由非造血细胞表达，是记忆性CD8 T细胞维持所必需的。据报道，在MHCII-/-和WT小鼠的脾脏中，IL-7和IL-15的mRNA表达水平是相当的。IL-7和IL-15是记忆性CD8 T细胞稳态的重要细胞因子。到目前为止，我们还没有发现MHCII-/-和WT小鼠血清中细胞因子、趋化因子和生长因子的不同表达水平。然而，对转染的CD8 T细胞在MHCII-/-和WT小鼠中表达的基因进行微阵列分析显示，有77种不同的基因表达水平。我们目前正试图揭示这些候选基因在记忆性CD8 T细胞维持中的功能。