Silencing ZAP70 prevents HSP65-induced reverse cholesterol transport and NF-κB activation in T cells

T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development. The zeta chain-associated 70-kDa protein (ZAP70) is sequentially activated in response to TCR engagement and serves as a critical component of the TCR signaling pathway, which is essential for T cell activation. However, some roles of ZAP70 have not been fully elucidated. In the present study, we analyzed the effects of ZAP70 on the cholesterol efflux rate, nuclear factor kappa B (NF-kappa B) activation and cell proliferation in T cells. Our study showed that silencing ZAP70 increased the cholesterol efflux rate in T cells. We also found that silencing ZAP enhanced the expression of ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), scavenger receptor-BI (SR-BI) peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and liver X receptor-alpha (LXR-alpha). In contrast, the phosphorylation of ZAP70 by HSP65 decreased the cholesterol efflux rate and the expression of five cholesterol transport proteins in T cells. The phosphorylation of ZAP70 activated the downstream NF-kappa B signaling pathway, which is involved in both T cell growth and function. Furthermore, silencing ZAP70 inhibited T cell proliferation. These results indicate a crucial and unexpected role for ZAP70 in the physiological activities of T cells, suggesting that inhibition of ZAP70 is beneficial for antiatherosclerosis.