| Summary: | Human CD56<sup>br</sup> natural killer (NK) cells represent a small subset of CD56<sup>+</sup> NK cells in circulation and are largely tissue-resident. The frequency and number of CD56<sup>br</sup> NK cells in blood has been shown to increase following administration of low-dose IL-2 (LD-IL2), a therapy aimed to specifically expand CD4<sup>+</sup> regulatory T cells (Tregs). Given the potential clinical application of LD-IL-2 immunotherapy across several immune diseases, including the autoimmune disease type 1 diabetes, a better understanding of the functional consequences of this expansion is urgently needed. In this study, we developed an <i>in vitro</i> co-culture assay with activated CD4<sup>+</sup> T cells to measure NK cell killing efficiency. We show that CD56<sup>br</sup> and CD56<sup>dim</sup> NK cells show similar efficiency at killing activated CD4<sup>+</sup> conventional T (Tconv) and Treg cell subsets. However, in contrast to CD56<sup>dim</sup> cells, CD56<sup>br</sup> NK cells preferentially target highly proliferative cells. We hypothesize that CD56<sup>br</sup> NK cells have an immunoregulatory role through the elimination of proliferating autoreactive CD4<sup>+</sup> Tconv cells that have escaped Treg suppression. These results have implications for the interpretation of current and future trials of LD-IL-2 by providing evidence for a new, possibly beneficial immunomodulatory mechanism of LD-IL-2-expanded CD56<sup>br</sup> NK cells.
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