The differential effects of type I IFN signaling on MHC class I and MHC class II–dependent GVHD and GVL responses. Signaling on host hematopoietic tissue decreases donor CD4 T-cell proliferation and differentiation via inhibitory effects on recipient APCs, resulting in reduced T-cell differentiation and GVHD of the colon. The inhibition of Th17 differentiation has been associated with inhibition of APC-derived osteopontin, which promotes IL-27 secretion. The signaling of donor APC by type I IFN promotes cross-presentation (ie, the presentation of exogenous recipient allogeneic peptides within MHC class I) and the expansion of donor CTLs. This effect is further amplified by direct signaling to donor NK and CD8 T cells, which together promote cytotoxicity (eg, mediated by perforin/granzyme) against GVHD target tissue and residual recipient leukemia (ie, GVL). Finally, the type I IFNs enhance the susceptibility of residual leukemia to CD8 and NK cell–mediated cytotoxicity, further amplifying GVL responses.