Increased cholesterol content in gammadelta (γδ) T lymphocytes differentially regulates their activation

PLoS One. 2013 May 21;8(5):e63746. doi: 10.1371/journal.pone.0063746. Print 2013.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cholesterol / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Intracellular Space / metabolism
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Phosphorylation
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / metabolism*


  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Antigen, T-Cell, gamma-delta
  • Cholesterol
  • Extracellular Signal-Regulated MAP Kinases