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LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation.


ABSTRACT: Cancer and chronic infections often increase levels of the bioactive lipid, lysophosphatidic acid (LPA), that we have demonstrated acts as an inhibitory ligand upon binding LPAR5 on CD8 T cells, suppressing cytotoxic activity and tumor control. This study, using human and mouse primary T lymphocytes, reveals how LPA disrupts antigen-specific CD8 T cell:target cell immune synapse (IS) formation and T cell function via competing for cytoskeletal regulation. Specifically, we find upon antigen-specific T cell:target cell formation, IP3R1 localizes to the IS by a process dependent on mDia1 and actin and microtubule polymerization. LPA not only inhibited IP3R1 from reaching the IS but also altered T cell receptor (TCR)–induced localization of RhoA and mDia1 impairing F-actin accumulation and altering the tubulin code. Consequently, LPA impeded calcium store release and IS-directed cytokine secretion. Thus, targeting LPA signaling in chronic inflammatory conditions may rescue T cell function and promote antiviral and antitumor immunity.

SUBMITTER: Kremer KN 

PROVIDER: S-EPMC9169816 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation.

Kremer Kimberly N KN   Buser Alan A   Thumkeo Dean D   Narumiya Shuh S   Jacobelli Jordan J   Pelanda Roberta R   Torres Raul M RM  

Proceedings of the National Academy of Sciences of the United States of America 20220408 15


Cancer and chronic infections often increase levels of the bioactive lipid, lysophosphatidic acid (LPA), that we have demonstrated acts as an inhibitory ligand upon binding LPAR5 on CD8 T cells, suppressing cytotoxic activity and tumor control. This study, using human and mouse primary T lymphocytes, reveals how LPA disrupts antigen-specific CD8 T cell:target cell immune synapse (IS) formation and T cell function via competing for cytoskeletal regulation. Specifically, we find upon antigen-speci  ...[more]

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