Interleukin-4:STAT6 signaling delays protective CD8 T cell bystander activation by antagonizing IL-18 sensing

Memory CD8 T cells (Tmem) are activated into innate-like killers by cytokines such as IL-12, IL-15 and IL-18; but mechanisms regulating this phenomenon (termed bystander activation) are unclear. We show that basal IL-4 signals antagonize IL-18 sensing and blunt IFNg production following bystander activation of Tmem in mice. Furthermore, IL-4 treatment can act directly on Tmem in a STAT6-dependent manner, to limit their control of a bystander bacterial infection. Nevertheless, we find that IL-4 does not simply block bystander activation but rather alters Tmem gene expression to tune effector molecule expression. Defective bystander activation of homeostatic Tmem in some strains relates, in part, to IL-4 exposure, but we show that these differences are erased in Tmem produced by TCR activation leading to uniform IL-18 receptor expression and capacity for bystander activation/cytotoxicity. Our data demonstrate that bystander activation by inflammatory cytokines is subject to regulation by both IL-4 and by prior antigen experience. These findings underscore the importance of the cytokine milieu in dictating the ability of bystander CD8 Tmem to mediate pathogen control.