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.