CD3ζ-Chain Expression of Human T Lymphocytes Is Regulated by TNF via Src-like Adaptor Protein-Dependent Proteasomal Degradation

Decreased expression of the TCR zeta-chain has been reported in several autoimmune, inflammatory, and malignant diseases, suggesting that zeta-chain downregulation is common at sites of chronic inflammation. Although zeta-chain is critically important in T lymphocyte activation, the mechanism of the decreased zeta-chain expression is less clear. Src-like adaptor protein (SLAP) is a master regulator of T cell activation; previous data have reported that SLAP regulates immunoreceptor signaling. We have examined the mechanism and the functional consequences of CD3 zeta-chain downregulation. TNF treatment of human T lymphocytes (15-40 ng/ml) selectively downregulates CD3 zeta-chain expression in a dose-dependent manner (p < 0.05) and decreases activation-induced IL-2 expression (p < 0.01). Although blocking of the lysosomal compartment fails to restore TNF-induced CD3 zeta-chain downregulation, inhibition of the proteasome prevented the effect of TNF. Both SLAP expression and the colocalization of SLAP with CD3 zeta-chain was enhanced by TNF treatment (p < 0.05 and p < 0.01, respectively), whereas TNF-induced zeta-chain downregulation was inhibited by gene silencing of SLAP with small interfering RNA. SLAP levels of the CD4(+) T lymphocytes isolated from patients with rheumatoid arthritis were more than 2-fold higher than that of the healthy donors' (p < 0.05); moreover, TNF treatment did not alter the SLAP expression of the CD4(+) cells of anti-TNF therapy-treated patients. Our present data suggest that TNF modulates T cell activation during inflammatory processes by regulating the amount of CD3 zeta-chain expression via a SLAP-dependent mechanism. These data provide evidence for SLAP-dependent regulation of CD3 zeta-chain in the fine control of TCR signaling. The Journal of Immunology, 2012, 189: 1602-1610.