Downregulation of CD3z in NK cells from systemic lupus erythematosus patients confers a proinflammatory phenotype

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3z, an important molecule for NK cell activation, is downregulated in SLE T cells and contributes to their altered function. However, little is known about the role of CD3z in SLE NK cells. We studied CD3z levels and its contribution to cytotoxic, degranulation, and cytokine production capacity of NK cells from patients with SLE. Furthermore, we studied the human NK cell line, NKL, in which manipulation of CD3z levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3z. We found reduced CD3z expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3z expression in NK cells is mediated, at least in part, by Caspase 3, the activity of which is higher in NK cells from patients with SLE compared with NK cells from healthy donors. CD3z levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN-g and TNF. In contrast, CD3z levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3z-silenced NKL and CD3z-deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3z levels. Our results demonstrate a differential role for CD3z in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3z confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE. The Journal of Immunology, 2018, 200: 3077–3086.