Weak SLP-76/PLC-γ1 interaction fine-tunes T cell receptor signal strength to optimize T cell responsiveness

Upon T cell receptor (TCR) engagement, phosphorylation of the LAT adapter protein enables binding of the enzyme PLC-γ1 to a Gads/SLP-76 dimer, forming a tetrameric structure. The interaction between SLP-76 and PLC-γ1 is weak within this heterotetramer, and the relevant binding sites of SLP-76 and PLC-γ1 are highly conserved in vertebrates. We generated a mouse with a T cell-specific mutation in the SLP-76 that enhanced its affinity for PLC-γ1, thereby increasing PLC-γ1 activity and TCR signal strength. This mutation not only altered the development of αβTCR thymocytes, invariant NKT cells, and intraepithelial lymphocyte precursors but also impaired the generation of central memory CD8⁺ T cells upon acute viral infection and the humoral immune response mediated by germinal center T follicular helper T cells. These findings suggest that the conserved weak SLP-76/PLC-γ1 interaction is important for the controlled activation of PLC-γ1, thus fine-tuning TCR signal strength to optimize T cell-mediated immunity.