Phosphoinositide acyl chain saturation drives CD8 effector T cell signaling and function.

How lipidome changes support CD8 effector T (T) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIP with 3-4 double bonds), T cells have unique PIP marked by saturated fatty acyl chains (0-2 double bonds). PIP are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP) exclusively supported signaling immediately upon T cell antigen receptor activation. In late T cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP into downstream mediators, waned, and saturated PIP became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIP impaired T cell fitness and function, even in cells with abundant polyunsaturated PIP. Glucose was the substrate for de novo PIP synthesis, and was rapidly utilized for saturated PIP generation. Thus, separate PIP pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.