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.