Reframing IL-27: a central regulator of CD8⁺ T cell immunity

Interleukin-27 (IL-27), a member of the IL-12 cytokine family, was long viewed primarily as a regulator of CD4⁺ T cell immunity. Subsequent studies revealed that IL-27 also directly modulates CD8⁺ T cells, displaying both stimulatory and inhibitory potential. Recent work extends this earlier literature, showing that IL-27 in infection and cancer can promote effector differentiation, sustain survival, and reverse dysfunction, often without the systemic toxicity associated with related cytokines. This review outlines the molecular features, signaling mechanisms, and cellular sources of IL-27, integrating emerging evidence from viral, tumor, and autoimmune settings. We propose that IL-27 operates not as an inherently pro- or anti-inflammatory cytokine but as a context-dependent tuner of CD8⁺ T cell cytotoxic immunity, offering new opportunities for therapeutic exploitation.