摘要

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)-susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell-intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.

译文

CD8，而不是 CD4，T 细胞被认为是控制慢性弓形虫病的关键。虽然 CD8 耗竭先前已在弓形虫脑炎 (TE) 易感模型中报告过, 我们目前的工作表明，CD4 不仅在慢性弓形虫病期间耗尽，而且这种功能障碍比 CD8 T 细胞更明显。耗竭的 CD4 人群表达了多种抑制受体水平的升高，同时伴随着功能的降低和转录因子 Blimp-1 的上调。我们的数据首次证明了 Blimp-1 是 CD4 T 细胞耗竭的关键调节因子，尤其是在 CD4 中央记忆细胞子集中。使用他莫昔芬依赖的条件性飞艇-1 基因敲除混合骨髓嵌合体以及过继转移方法, 我们表明，CD4 T 细胞固有的 Blimp-1 缺失逆转了 CD8 T 细胞功能障碍，并改善了病原体控制。据我们所知，这是一个新颖的发现, 它证明了 Blimp-1 作为 CD4 功能障碍的关键调节器的作用，并将其与在感染小鼠中观察到的 CD8 T 细胞功能障碍联系起来。CD4-intrinsic Blimp-1 表达在介导 CD4 和 CD8 T 细胞耗竭中的关键作用可能为设计新的治疗方法提供合理的基础。