γc receptor antagonist, EQ102, prevents the NK and T cell-mediated responses driven by IL-15 and IL-21

Abstract

Abstract Synergistic signaling of IL-15 and IL-21 is important in driving pathogenic T and NK cell responses in multiple inflammatory diseases. IL-15 and IL-21 are part of the common gamma chain (γc) cytokine family, which use the shared γc receptor subunit in their signaling complexes. IL-15 and IL-21 each promote cytolytic activity and IFNγ production but can also synergistically enhance the function of other cytotoxic cytokines. Consequently, blockade of IL-15 or IL-21 alone is likely insufficient to improve disease outcome in pathologic environments. EQ102 is a multi-cytokine inhibitor that selectively blocks IL-15 and IL-21 signaling while preserving signaling of other γc family members. Here, we sought to investigate the effect of synergistic signaling from both IL-15 and IL-21 on NK and T cell activities and the ability of EQ102 to inhibit these signals and resultant cellular response. PBMCs from healthy donors or NK-92 cells were incubated with EQ102 for 1 hour and then stimulated with IL-15, IL-21, or in combination. Following stimulation, cellular expression of transcription factors and activation markers were analyzed by flow cytometry. Cell supernatant was assessed for T and NK cell cytokines. IL-15 stimulation increases proliferation of T and NK cells, where IL-21 had a modest effect. However, co-stimulation of IL-15 and IL-21 enhanced proliferation, activation, and upregulation of IFNγ production over single cytokine IL-15 conditions. EQ102 treatment effectively inhibits the IL-15/IL-21 co-stimulatory cytolytic responses of these cell populations. These results suggest that selective blockade of IL-15 and IL-21 by EQ102 inhibits the synergistic signaling that mediates NK and T cell responses in multiple immune disorders. None