Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease 
characterized by multiple cellular and molecular dysfunctions of the innate and 
adaptive immunity. Cytotoxic function of NK cells is compromised in patients 
with SLE. Herein, we characterized the phenotypic alterations of SLE NK cells in 
a comprehensive manner to further delineate the mechanisms underlying the 
cytotoxic dysfunction of SLE NK cells and identify novel potential therapeutic 
targets. Therefore, we examined PBMC from SLE patients and matched healthy 
controls by single-cell mass cytometry to assess the phenotype of NK cells. In 
addition, we evaluated the cell function of NK cells (degranulation and cytokine 
production) and the killing of B cell subpopulations in a B cell-NK cell in 
vitro co-culture model. We found that SLE NK cells expressed higher levels of 
CD38 and were not able to adequately upregulate SLAMF1 and SLAMF7 following 
activation. In addition, ligation of SLAMF7 with elotuzumab or of CD38 with 
daratumumab on SLE NK cells enhanced degranulation of both healthy and SLE NK 
cells and primed them to kill circulating plasma cells in an in vitro co-culture 
system. Overall, our data indicated that dysregulated expression of CD38, SLAMF1 
and SLAMF7 on SLE NK cells is associated with an altered interplay between SLE 
NK cells and plasma cells, thus suggesting their contribution to the 
accumulation of (auto)antibody producing cells. Accordingly, targeting SLAMF7 
and CD38 may represent novel therapeutic approaches in SLE by enhancing NK cell 
function and promoting elimination of circulating plasma cell.