Journal Article

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

Maib, Hannes, Paul, Harry, Martin, Jacob, Sanin, David E., Flachsmann, Lea, Zeiser, Robert, Pearce, Erika L., O’Sullivan, David, Edwards-Hicks, Joy, Soballa, Melanie, Klein Geltink, Ramon I., Pearce, Edward J., Buescher, Joerg M., Maccari, Maria Elena, Curtis, Jonathan D., Baixauli, Francesc, Haessler, Fabian, Apostolova, Petya, Field, Cameron S., Meiss, Frank, Caputa, George, Kyle, Ryan L., Kelly, Beth, Winkler, Frances, Cha, Minsun, Rafei-Shamsabadi, David Ali, Mitterer, Michael, Corrado, Mauro, Villa, Matteo, Stanczak, Michal A., Grzes, Katarzyna M., Bengsch, Bertram, Zhao, Liang, Carrizo, Gustavo E., Patterson, Annette, Puleston, Daniel J.

2023

Overview

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. Here the authors show how metabolic alteration of acyl chain composition affects phosphoinositide-driven signaling to initiate and sustain CD8 + T cell effector function during cell differentiation.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554/1834 / 631/250/2152/1566/1618 / 631/250/516 / 631/45 / Biomedical and Life Sciences / Biomedicine / CD8 antigen / CD8-Positive T-Lymphocytes - metabolism / Cell activation / Cell differentiation / Cell signaling / Immunology / Infectious Diseases / Lymphocytes / Lymphocytes T / Metabolism / Phosphatidylinositol / Phosphatidylinositol 4,5-diphosphate / Phosphatidylinositol Phosphates / Phosphatidylinositols - metabolism / Phosphoinositides / Phospholipase / Phospholipase C / Receptor mechanisms / Second messengers / Signal Transduction / Type C Phospholipases - metabolism