Fuse Shinichiro, Tsai Ching-Yi, Molloy Michael J, Allie S Rameeza, Zhang Weijun, Yagita Hideo, Usherwood Edward J
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
J Immunol. 2009 Apr 1;182(7):4244-54. doi: 10.4049/jimmunol.0802041.
CD4 help is crucial for memory CD8(+) T cell development, yet the mechanisms of CD4 help and why (CD4) helpless memory CD8(+) T cells elicit poor recall responses are currently not well understood. In this study we investigated these questions using an in vivo acute virus infection model. We show herein that CD4 help during priming is required for memory CD8(+) T cell differentiation, and that stimulation of CD40 during priming rescues the helpless defects in the absence of CD4(+) T cells. The defective recall response by helpless memory cells did not correlate with the amount of cell death and was independent of TRAIL. However, helpless memory cells excessively up-regulated the inhibitory receptor PD-1 (programmed cell death-1), and PD-1 blockade enhanced the recall response of helpless memory cells. Furthermore, providing IL-2 signaling in vivo during the recall response reduced PD-1 expression and rescued the recall response of helpless memory cells. Our study identifies molecular pathways involved in CD4 help for memory CD8(+) T cell generation that are independent of TRAIL, and it provides therapeutic implications that helpless memory cell function can be restored at multiple stages through various immunological interventions.
CD4辅助对于记忆性CD8(+) T细胞的发育至关重要，然而目前对于CD4辅助的机制以及为何（CD4）缺失型记忆性CD8(+) T细胞引发的回忆反应较差尚不清楚。在本研究中，我们使用体内急性病毒感染模型对这些问题进行了研究。我们在此表明，初次免疫期间的CD4辅助对于记忆性CD8(+) T细胞的分化是必需的，并且在初次免疫期间刺激CD40可在缺乏CD4(+) T细胞的情况下挽救缺失型缺陷。缺失型记忆细胞有缺陷的回忆反应与细胞死亡量无关，且不依赖于肿瘤坏死因子相关凋亡诱导配体（TRAIL）。然而，缺失型记忆细胞过度上调抑制性受体程序性死亡蛋白1（PD-1），而阻断PD-1可增强缺失型记忆细胞的回忆反应。此外，在回忆反应期间在体内提供白细胞介素-2信号可降低PD-1表达并挽救缺失型记忆细胞的回忆反应。我们的研究确定了与记忆性CD8(+) T细胞生成的CD4辅助相关的独立于TRAIL的分子途径，并提供了通过各种免疫干预可在多个阶段恢复缺失型记忆细胞功能的治疗意义。
