IL-27 maintains cytotoxic Ly6C⁺ γδ T cells that arise from immature precursors

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αβ-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27⁺ Ly6C^- cells convert into CD27⁺Ly6C⁺ cells, and these CD27⁺Ly6C⁺ cells control cancer progression in mice, while the CD27⁺Ly6C^- cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27⁺Ly6C⁺ cells and human Vδ2⁺ cells, while IL-27 is dispensable for mouse CD27⁺Ly6C^- cell and human Vδ1⁺ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.