Downregulation of CD3ζ in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype

Abstract

Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3ζ, 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 CD3ζ in SLE NK cells. We studied CD3ζ 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 CD3ζ levels was achieved using small interfering RNA and NK cells from mice deficient in CD3ζ. We found reduced CD3ζ expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3ζ 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. CD3ζ levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN-γ and TNF. In contrast, CD3ζ levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3ζ-silenced NKL and CD3ζ-deficient NK cells from mice confirmed the dependence of NK cell function on CD3ζ levels. Our results demonstrate a differential role for CD3ζ in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3ζ confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE.

NK Cells in Autoimmune Diseases: Protective or Pathogenic?

“…Recent studies have investigated the direct cytotoxic action and cytokine profiles of NK cells in the pathogenesis of SLE. For example, the increased cytotoxicity and proinflammatory phenotype of NK cells was shown to be correlated with downregulation of CD3ξ expression in patients with SLE (48); the authors also demonstrated that caspase-3 activity was higher in NK cells from patients with SLE than those from healthy controls and that this contributed to the downregulation of CD3ξ expression in the cells, which enhanced their proinflammatory phenotype.…”

Defects at the Posttranscriptional Level Account for the Low TCRζ Chain Expression Detected in Gastric Cancer Independently of Caspase-3 Activity

“…Moreover, Western blot analysis (which detects total protein amount and not just membrane-bound) showed that in patients with low TCR ζ levels, CD3 ε expression was like that of healthy individuals, indicating that its biosynthesis is not affected. Interestingly, previous analysis carried out on NK cells from SLE patients [ 6 ] revealed a diminished expression of CD3 ζ with no effect on other molecules such as NKp30 and NKp46, which also signal via CD3 ζ .…”

“…We then went on analyzing caspase-3 activity, involved by some authors in low TCR ζ expression [ 6 , 7 ]. In keeping with previous published data, our results revealed higher enzymatic activity in T cells from patients when compared to control subjects, activity which could be diminished (by 70%) using the Ac-DEVD-FMK inhibitor.…”

“…Downregulation of T cell receptor- (TCR-) associated cell surface proteins, such as TCR ζ (CD247) [ 5 ], is one of such alterations. This downregulation was found not only in cancer but also in other inflammatory conditions, as systemic lupus erythematosus, (SLE [ 6 , 7 ]) amongst others.…”

LncRNA XIST alters the balance of peripheral blood immune cells in systemic lupus erythematosus by regulating the miR-17-92, OFLM4 and CEACAM8 axis

“…Like Treg cells, the number of NK cells was signi cantly decreased in patients with active SLE [26]. However, Suárez-Fueyo et al [27] reported that NK cells in SLE patients exhibited increased cytotoxicity and pro-in ammatory phenotypes that were associated with down-regulation of CD3ζ. These observations are consistent with the present ndings.…”