Downregulation of CD3{zeta} in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype [AUTOIMMUNITY]

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3, 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 CD3 in SLE NK cells. We studied CD3 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 CD3 levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3. We found reduced CD3 expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3 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. CD3 levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN- and TNF. In contrast, CD3 levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3-silenced NKL and CD3-deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3 levels. Our results demonstrate a differential role for CD3 in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3 confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE.

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