Sprouty-2 regulates HIV-specific T cell polyfunctionality
Sprouty-2 regulates HIV-specific T cell polyfunctionality
复制标题
DOI：
10.1172/jci70510
复制
发表时间：
2014-01-01
影响因子：
15.9
通讯作者：
Schneck, Jonathan P.
中科院分区：
文献类型：
--
作者：
Chiu, Yen-Ling;Shan, Liang;Schneck, Jonathan P.
单个T细胞执行多种效应功能的能力对于针对病毒和癌症的保护性免疫至关重要。这种多功能性在慢性感染期间经常丢失;然而，驱动T细胞多功能性的分子机制知之甚少。我们发现，由高浓度的抗原刺激的人T细胞缺乏多功能性，并表达与耗尽的T细胞相似的转录谱。与控制T细胞多功能性的转录谱有关的一个特定途径是MAPK/ERK途径。该途径响应于不同的抗原浓度而改变，并且多功能性与磷酸化的上调相关。埃里克用高浓度抗原刺激的T细胞上调sprougty-2（SPRY 2），SPRY 2是MAPK/ERK途径的负调节剂。SPRY 2的临床相关性通过检查HIV特异性T细胞中的SPRY 2表达来证实，其中在HIV特异性T细胞中观察到高水平的SPRY 2，并且SPRY 2表达的抑制增强了独立于PD-1途径的HIV特异性多功能应答。我们的发现表明，在慢性病毒感染过程中SPRY 2表达的增加降低了T细胞的多功能性，并将SPRY 2确定为免疫治疗的潜在靶点。
The ability of individual T cells to perform multiple effector functions is crucial for protective immunity against viruses and cancer. This polyfunctionality is frequently lost during chronic infections; however, the molecular mechanisms driving T cell polyfunctionality are poorly understood. We found that human T cells stimulated by a high concentration of antigen lacked polyfunctionality and expressed a transcription profile similar to that of exhausted T cells. One specific pathway implicated by the transcription profile in control of T cell polyfunctionality was the MAPK/ERK pathway. This pathway was altered in response to different antigen concentrations, and polyfunctionality correlated with upregulation of phosphorylated. ERK. T cells that were stimulated with a high concentration of antigen upregulated sprouty-2 (SPRY2), a negative regulator of the MAPK/ERK pathway. The clinical relevance of SPRY2 was confirmed by examining SPRY2 expression in HIV-specific T cells, where high levels of SPRY2 were seen in HIV-specific T cells and inhibition of SPRY2 expression enhanced the HIV-specific polyfunctional response independently of the PD-1 pathway. Our fmdings indicate that increased SPRY2 expression during chronic viral infection reduces T cell polyfunctionality and identify SPRY2 as a potential target for immunotherapy.