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 (PIP₂) exclusively supported signaling immediately upon T cell antigen receptor activation. In late T_eff cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP₂ into downstream mediators, waned, and saturated PIP_n became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP₂ 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 PIP₂ 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.