In vivo maturation of allo-specific CD8 CTL and prevention of lupus-like graft-versus-host disease is critically dependent on T cell signaling through the TNF p75 receptor but not the TNF p55 receptor.
In vivo maturation of allo-specific CD8 CTL and prevention of lupus-like graft-versus-host disease is critically dependent on T cell signaling through the TNF p75 receptor but not the TNF p55 receptor.
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DOI：
10.4049/jimmunol.1300091
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Via CS
中科院分区：
文献类型：
--
作者：
Soloviova K;Puliaiev M;Haas M;Via CS
除了TCR和CD 28接合之外，效应CD 8 CTL的成熟还需要第三个信号。炎性细胞因子可以提供第三信号，然而在非病原体环境中（即抗肿瘤反应），第三信号的身份不清楚。在不存在外源性病原体的情况下，体内CD 8 CTL的有用模型是同种异体抗原驱动的亲本进入F1的急性移植物抗宿主疾病（GVHD），其特征在于强的TNF依赖性供体抗宿主CD 8 CTL T细胞应答。为了确定TNF是否以信号3方式直接作用于供体T细胞，F1小鼠接受TNF受体p55敲除（KO）和/或p55 KO供体T细胞。供体p75 K而不是p55 KO供体T细胞不能诱导急性GVHD表型，而是由于定量和定性的供体T细胞缺陷，即减少的穿孔素、IFN-g和TNF产生，诱导了短期和长期的狼疮样慢性GVHD。从WT或p75 KO供体转移混合或匹配的纯化的CD 4和CD 8 T细胞表明，最佳CTL成熟需要CD 4和CD 8 T细胞中的p75信号传导。尽管有缺陷的p75 KO CD 4帮助CD 8 CTL，但p75 KO CD 4帮助B细胞和自身免疫是完整的。这些结果提供了一种机制，通过这种机制，受损的CD 8 CTL可能有助于降低接受TNF阻断剂的患者的抗病毒和抗肿瘤应答以及自身免疫。我们的研究结果支持这样的观点，即选择性p55阻断可能通过减少炎症而不损害CD 8 CTL而有益。
A third signal is required for maturation of effector CD8 CTL in addition to TCR and CD28 engagement. Inflammatory cytokines can provide a third signal however in non-pathogen settings (i.e. anti-tumor responses), the identity of the third signal is not clear. A useful model for in vivo CD8 CTL in the absence of exogenous pathogens is the alloantigen driven parent-into F1 model of acute graft-vs.-host disease (GVHD) characterized by a strong TNF-dependent donor anti-host CD8 CTL T cell response. To determine whether TNF acts directly on donor T cells in a signal 3 manner, F1 mice received TNF receptor p55 knock out (KO) and/or p55 KO donor T cells. Donor p75 K but not p55 KO donor T cells failed to induce acute GVHD phenotype and instead induced a lupus-like chronic GVHD both short and long term due to quantitative and qualitative donor T cell defects i.e. reduced perforin, IFN-g and TNF production. Transfer of mixed or matched purified CD4 and CD8 T cells from WT or p75KO donors demonstrated that optimal CTL maturation required p75 signaling in both CD4 and CD8 T cells. Despite defective p75 KO CD4 help for CD8 CTL, p75KO CD4 help for B cells and autoimmunity was intact. These results provide a mechanism by which impaired CD8 CTL could contribute to reduced anti-viral and anti-tumor responses and autoimmunity reported in patients receiving TNF blockers. Our results support the idea that selective p55 blockade may be beneficial by reducing inflammation without compromising CD8 CTL.
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DOI：
10.1084/jem.20020223
发表时间：
2002-09-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fan GC;Singh RR
通讯作者：
Singh RR
影响因子：
7
作者：
Curtsinger JM;Mescher MF
通讯作者：
Mescher MF
DOI：
10.1016/j.clim.2010.01.005
发表时间：
2010-07
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Foster AD;Haas M;Puliaeva I;Soloviova K;Puliaev R;Via CS
通讯作者：
Via CS
影响因子：
12.8
作者：
Eisenberg RA;Via CS
通讯作者：
Via CS
影响因子：
56.9
作者：
Badovinac, VP;Tvinnereim, AR;Harty, JT
通讯作者：
Harty, JT