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

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

    Research output: Contribution to journalArticlepeer-review

    5 Citations (Scopus)

    Abstract

    How lipidome changes support CD8+ effector T (Teff) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIPn with 3-4 double bonds), Teff cells have unique PIPn marked by saturated fatty acyl chains (0-2 double bonds). PIPn are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP2) exclusively supported signaling immediately upon T cell antigen receptor activation. In late Teff cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP2 into downstream mediators, waned, and saturated PIPn became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP2 with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIPn impaired Teff cell fitness and function, even in cells with abundant polyunsaturated PIPn. Glucose was the substrate for de novo PIPn synthesis, and was rapidly utilized for saturated PIP2 generation. Thus, separate PIPn 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.

    Original languageEnglish
    Pages (from-to)516-530
    Number of pages15
    JournalNature Immunology
    Volume24
    Early online date2 Feb 2023
    DOIs
    Publication statusPublished - Mar 2023

    Keywords

    • Biochemistry
    • CD8-positive T cells
    • Lymphocyte activation
    • Signal transduction

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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