Increased Cholesterol Content in Gammadelta

• Published in: PloS one 2013-05, Vol.8 (5), p.e63746
• Main Authors: Cheng, Hsin-Yuan, Wu, Runpei, Gebre, Abraham K, Hanna, Richard N, Smith, Dan J, Parks, John S, Ley, Klaus, Hedrick, Catherine C
• Format: Article
• Language: English
• Subjects: Antigens; Cholesterol; Physiological aspects; T cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063746

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][delta] 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.