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

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

doi:10.1038/s41590-023-01419-y

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

MPS-Authors

Edwards-Hicks, Joy
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Apostolova, Petya
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Büscher, Jörg Martin
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Stanczak, Michal A
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Corrado, Mauro
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Geltink, Ramon I Klein
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Villa, Matteo
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Carrizo, Gustavo E
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sanin, David E
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Baixauli, Francesc
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kelly, Beth
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Curtis, Jonathan D
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Haessler, Fabian
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Patterson, Annette
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Field, Cameron S
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Caputa, George
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kyle, Ryan L
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Soballa, Melanie
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Grzes, Katarzyna M
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Flachsmann, Lea
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Mitterer, Michael
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Puleston, Daniel J
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

O'Sullivan, David
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pearce, Edward Jonathen
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201431

Pearce, Erika Laine
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.nature.com/articles/s41590-023-01419-y
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10.1038_s41590-023-01419-y.pdf
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Citation

Edwards-Hicks, J., Apostolova, P., Büscher, J. M., Maib, H., Stanczak, M. A., Corrado, M., et al. (2023). Phosphoinositide acyl chain saturation drives CD8⁺ effector T cell signaling and function. Nature Immunology, 24, 516-530. doi:10.1038/s41590-023-01419-y.

Cite as: https://hdl.handle.net/21.11116/0000-000D-12D6-D

Abstract

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.