Uncovering a novel role of PLC beta 4 in selectively mediating TCR signaling in CD8(+) but not CD4(+) T cells

Abstract

Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4(+) and CD8(+) T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8(+) T cells is qualitatively different from that in CD4(+) T cells, since CD8 alpha ignites another cardinal signaling cascade involving phospholipase C beta 4 (PLC beta 4). TCR-mediated responses were severely impaired in PLC beta 4-deficient CD8(+) T cells, whereas those in CD4(+) T cells were intact. PLC beta 4-deficient CD8(+) T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLC beta 4 to the cytoplasmic tail of CD8 alpha was important for CD8(+) T cell activation. Furthermore, GNAQ interacted with PLC beta 4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLC beta 4, and activated CD8(+) T cells in a PLC beta 4-dependent fashion. PLC beta 4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLC beta 4 differentiates TCR signaling in CD4(+) and CD8(+) T cells and selectively promotes CD8(+) T cell-dependent adaptive immunity.