CD8+ T cells serve on the front line in battling tumors. In Nature, Xu and colleagues show that modulation of membrane cholesterol content can enhance the anti-tumor response by CD8+ T cells. Inhibition or deletion of the gene encoding the cholesterol-esterification enzyme ACAT1 leads to enhanced effector function of CD8+ T cells, including increased production of cytokines and granzymes in vitro and anti-tumor responses in vivo. Acat1 is upregulated after activation of the T cell antigen receptor (TCR) in CD8+ T cells but not in CD4+ T cells. This response is concomitant with a reduction in the plasma-membrane cholesterol content, suggestive of a negative feedback mechanism for TCR signaling in immunological synapses. This hypothesis is supported by the enhanced formation of TCR microclusters and activation of downstream signaling components observed in the ACAT1-deficient CD8+ T cells. The findings suggest that modulation of cholesterol metabolism might have therapeutic benefits for promoting anti-tumor responses in the clinic.

Nature (16 March 2016) doi:10.1038/nature17412