title: Increased cholesterol content in gammadelta (γδ) T lymphocytes differentially regulates their activation.
abstract: Gammadelta (γδ) T lymphocytes respond quickly upon antigen encounter to produce a cytokine response. In this study, we sought to understand how functions of γδ T cells are differentially regulated compared to αβ T cells. We found that cholesterol, an integral component of the plasma membrane and a regulator of TCR signaling, is increased in γδ T cells compared to αβ T cells, and modulates their function. Higher levels of activation markers, and increased lipid raft content in γδ cells suggest that γδ T cells are more activated. Cholesterol depletion effectively decreased lipid raft formation and activation of γδ T cells, indicating that increased cholesterol content contributes to the hyper-activated phenotype of γδ T cells, possibly through enhanced clustering of TCR signals in lipid rafts. TCR stimulation assays and western blotting revealed that instead of a lower TCR threshold, enhanced TCR signaling through ERK1/2 activation is likely the cause for high cholesterol-induced rapid activation and proliferation in γδ T cells. Our data indicate that cholesterol metabolism is differentially regulated in γδ T cells. The high intracellular cholesterol content leads to enhanced TCR signaling and increases activation and proliferation of γδ T cells.
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, La Jolla, California, United States of America.
authors.forename: Hsin-Yuan
authors.initials: HY
authors.lastname: Cheng
authors.forename: Runpei
authors.initials: R
authors.lastname: Wu
authors.forename: Abraham K
authors.initials: AK
authors.lastname: Gebre
authors.forename: Richard N
authors.initials: RN
authors.lastname: Hanna
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Smith
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D042541:Intracellular Space / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010766:Phosphorylation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases