Yao Yichen, Zhang Zelu, Wang Shicheng, Wang Junjun, Hao Yuankai, Wang Ke, Liu Ping
School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Cells. 2025 Apr 21;14(8):620. doi: 10.3390/cells14080620.
CD4 T cells have been well-regarded as "helper" cells in activating the cytotoxicity of CD8 T cells for effective tumor eradication, while few studies have focused on whether CD8 T cells regulate CD4 T cells. Our previous studies provided evidence for an interaction between CD4 and CD8 T cells after cryo-thermal therapy, but the mechanism remains unclear, especially pertaining to how CD8 T cells promote the Th1 differentiation of CD4 T cells. This study revealed that activated CD4 and CD8 T cells are critical for CTT-induced antitumor immunity, and the interaction between activated T cells is enhanced. The reciprocal regulation of activated CD8 and CD4 T cells was through LFA-1/ICAM-1 interactions, in which CD8 T cells facilitate Notch1-dependent CD4 Th1-dominant differentiation and promote IL-2 secretion of CD4 T cells. Meanwhile, IL-2 derived from CD4 T cells enhances the cytotoxicity of CD8 T cells and establishes a positive feedback loop via increasing the expression of LFA-1 and ICAM-1 on T cells. Clinical analyses further validated that LFA-1/ICAM interactions between CD4 and CD8 T cells are correlated with clinical outcomes. Our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in the interaction of CD4 and CD8 T cells.
CD4 T细胞在激活CD8 T细胞的细胞毒性以有效根除肿瘤方面一直被视为“辅助”细胞，而很少有研究关注CD8 T细胞是否调节CD4 T细胞。我们之前的研究为冷冻热疗后CD4和CD8 T细胞之间的相互作用提供了证据，但具体机制仍不清楚，尤其是CD8 T细胞如何促进CD4 T细胞向Th1分化。本研究表明，活化的CD4和CD8 T细胞对冷冻热疗诱导的抗肿瘤免疫至关重要，并且活化T细胞之间的相互作用增强。活化的CD8和CD4 T细胞的相互调节是通过LFA-1/ICAM-1相互作用实现的，其中CD8 T细胞促进Notch1依赖的CD4 Th1优势分化，并促进CD4 T细胞分泌IL-2。同时，CD4 T细胞衍生的IL-2增强了CD8 T细胞的细胞毒性，并通过增加T细胞上LFA-1和ICAM-1的表达建立了一个正反馈回路。临床分析进一步证实，CD4和CD8 T细胞之间的LFA-1/ICAM相互作用与临床结果相关。我们的研究扩展了LFA-1/ICAM-1黏附途径的功能，表明其在CD4和CD8 T细胞相互作用中的新作用。
