Uncovering a novel role of PLCβ4 in selectively mediating TCR signaling in CD8(+) but not CD4(+) T cells

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 CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8(+) T cells, whereas those in CD4(+) T cells were intact. PLCβ4-deficient CD8(+) T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP(3) generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8(+) T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8(+) T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4(+) and CD8(+) T cells and selectively promotes CD8(+) T cell–dependent adaptive immunity.