Increased Cholesterol Content in Gammadelta (γδ) T Lymphocytes Differentially Regulates Their Activation

Gammadelta (gamma delta) T lymphocytes respond quickly upon antigen encounter to produce a cytokine response. In this study, we sought to understand how functions of gamma delta T cells are differentially regulated compared to alpha beta T cells. We found that cholesterol, an integral component of the plasma membrane and a regulator of TCR signaling, is increased in gamma delta T cells compared to alpha beta T cells, and modulates their function. Higher levels of activation markers, and increased lipid raft content in gamma delta cells suggest that gamma delta T cells are more activated. Cholesterol depletion effectively decreased lipid raft formation and activation of gamma T cells, indicating that increased cholesterol content contributes to the hyper-activated phenotype of gamma delta 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 gamma delta T cells. Our data indicate that cholesterol metabolism is differentially regulated in gamma delta T cells. The high intracellular cholesterol content leads to enhanced TCR signaling and increases activation and proliferation of gamma delta T cells.