LFA-1/ICAM-1 Interactions Between CD8+ and CD4+ T Cells Promote CD4+ Th1-Dominant Differentiation and CD8+ T Cell Cytotoxicity for Strong Antitumor Immunity After Cryo-Thermal Therapy

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.