Significance IFN-γ is an example of a pleiotropic cytokine that plays critical roles in promoting both protective immune responses and immunopathological processes. In response to this cytokine, cells activate a well-identified and conserved JAK/STAT signaling pathway that can still elicit distinct responses, even in the same cell type. How this outcome specificity is achieved remains largely unknown. We have found that IFN-γ regulates CD8 T cell differentiation through noncanonical pathways that are enabled by integrin costimulation of the STAT1 pathway. This leads to cooperative effects between activating cell types that is dictated by proximity. This study demonstrates the importance of cofactors and microenvironment in eliciting specific cytokine functions.