CD56^bright natural killer cells preferentially kill proliferating CD4⁺ T cells

Human CD56^br natural killer (NK) cells represent a small subset of CD56⁺ NK cells in circulation and are largely tissue-resident. The frequency and number of CD56^br 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⁺ 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 in vitro co-culture assay with activated CD4⁺ T cells to measure NK cell killing efficiency. We show that CD56^br and CD56^dim NK cells show similar efficiency at killing activated CD4⁺ conventional T (Tconv) and Treg cell subsets. However, in contrast to CD56^dim cells, CD56^br NK cells preferentially target highly proliferative cells. We hypothesize that CD56^br NK cells have an immunoregulatory role through the elimination of proliferating autoreactive CD4⁺ 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^br NK cells.