IL-2 and TGF-b1 promote regulatory activity in NK cells following Hematopoietic Stem Cell Transplantation

Natural Killer(NK) cell activity is influenced by cytokines and microenvironment factors, resulting in remarkably diverse functions ranging from contributing to inflammatory responses to instead inhibiting T cell and B cell activity, thereby serving as rheostats of adaptive immunity. Using scRNAseq, we identified a TGFb1highCD56brightNK cell population associated with protection from acute Graft-versus-Host Disease. We further define a role for the combination of IL-2 and TGF-b in promoting NK cells to acquire a regulatory phenotype. ‘Induced’ regulatory NK cells produce high amounts of TGF-b1, inhibited T cells, could promote naïve T cells differentiation into regulatory T cells, and exhibited a unique transcriptional program that includes expression of IKZF2(HELIOS) and ZNF683(HOBIT). This phenotype was not stable, and induced regulatory NK cells lost the ability to secrete TGF-b1 upon exposure to different cytokines. These findings define protective CD56brightNK cells in Hematopoietic Stem Cell Transplant, and support IL-2 and TGF-b1 promote regulatory NK cells.