LFA-1 regulates CD8+ T cell activation through both TCR-mediated and LFA-1-mediated Erk1/2 signal pathways (35.16)

Abstract

Abstract LFA-1 regulates T cell activation and signal transduction through the immunological synapse. TCR stimulation rapidly activates LFA-1, which provides unique LFA-1-dependent signals to promote T cell activation. However, the detailed molecular pathway and the precise mechanism by which LFA-1 contributes to TCR activation remain unclear. Herein, we report that LFA-1 directly participates in Erk1/2 signaling upon TCR stimulation in CD8+ T cells. The presence of LFA-1, not ligand binding, is required for the TCR-mediated Erk1/2 signal pathway. LFA-1-deficient CD8+ T cells have defects in sustained Erk1/2 signaling and TCR/CD3 clustering, which subsequently prevents MTOC re-orientation, cell-cycle progression and mitosis. LFA-1 regulates the TCR-mediated Erk1/2 signal pathway in the context of immunological synapse for recruitment and amplification of Erk1/2 signal. Furthermore, LFA-1 ligation with ICAM-1 generates an additional Erk1/2 signal, which synergizes with the existing TCR-mediated Erk1/2 signal to enhance T cell activation. The LFA-1-mediated Erk1/2 signal pathway is independent of ZAP-70 and PI3K but partially depends on Lck. Thus, LFA-1 contributes to CD8+ T cell activation through two distinct signal pathways. The function of LFA-1 is to enhance TCR signaling through the immunological synapse and deliver distinct signal in CD8+ T cell activation.