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

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