Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling.
Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling.
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DOI：
10.1084/jem.185.9.1573
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发表时间：
1997-05-05
期刊：
影响因子：
--
通讯作者：
McDevitt HO
中科院分区：
文献类型：
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作者：
Cope AP;Liblau RS;Yang XD;Congia M;Laudanna C;Schreiber RD;Probert L;Kollias G;McDevitt HO
成年小鼠反复注射重组鼠TNF可延长NZB/W F1小鼠的生存期，并抑制非肥胖糖尿病（NOD）小鼠的I型胰岛素依赖性糖尿病（IDDM）。为了确定反复注射TNF是否抑制成年小鼠的T细胞功能，我们研究了来自T细胞受体（HNT-TCR）转基因小鼠的流感血凝素特异性T细胞的反应。用鼠TNF治疗成年小鼠3周抑制了广泛的T细胞应答，包括增殖和细胞因子产生。此外，与HNT-TCR单转基因同窝出生的小鼠相比，也表达人TNF-珠蛋白转基因的HNT-TCR转基因小鼠的T细胞应答显著降低，表明持续的p55 TNF-R信号传导足以抑制体内T细胞功能。使用体外慢性TNF暴露模型，我们证明：（a）慢性TNF效应是剂量和时间依赖性的，（B）TNF抑制Th 1和Th 2辅助性T细胞亚群的反应，（c）T细胞培养物中产生的内源性TNF的抑制作用可以用TNF的中和性单克隆抗体逆转，和（d）长期TNF暴露减弱T细胞受体信号传导。体内抗TNF治疗增强T细胞增殖反应和细胞因子产生的发现为TNF对健康实验室小鼠T细胞的新调节作用提供了证据。这些作用在慢性炎症性疾病中更为明显。此外，我们的数据提供了一种机制，通过这种机制，长期的TNF暴露抑制疾病的动物模型的自身免疫。
Repeated injections of adult mice with recombinant murine TNF prolong the survival of NZB/W F1 mice, and suppress type I insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. To determine whether repeated TNF injections suppress T cell function in adult mice, we studied the responses of influenza hemagglutinin-specific T cells derived from T cell receptor (HNT-TCR) transgenic mice. Treatment of adult mice with murine TNF for 3 wk suppressed a broad range of T cell responses, including proliferation and cytokine production. Furthermore, T cell responses of HNT-TCR transgenic mice also expressing the human TNF-globin transgene were markedly reduced compared to HNT-TCR single transgenic littermates, indicating that sustained p55 TNF-R signaling is sufficient to suppress T cell function in vivo. Using a model of chronic TNF exposure in vitro, we demonstrate that (a) chronic TNF effects are dose and time dependent, (b) TNF suppresses the responses of both Th1 and Th2 T helper subsets, (c) the suppressive effects of endogenous TNF produced in T cell cultures could be reversed with neutralizing monoclonal antibodies to TNF, and (d) prolonged TNF exposure attenuates T cell receptor signaling. The finding that anti-TNF treatment in vivo enhances T cell proliferative responses and cytokine production provides evidence for a novel regulatory effect of TNF on T cells in healthy laboratory mice. These effects are more pronounced in chronic inflammatory disease. In addition, our data provide a mechanism through which prolonged TNF exposure suppresses disease in animal models of autoimmunity.