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

In mice, γδ T cells that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage in the thymus, and in the periphery, these cells play a critical role in host defence 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 immature CD27⁺Ly6C^—cells convert into mature CD27⁺Ly6C⁺cells, and these mature cells control cancer progression while the immature 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^—cells and human Vδ1⁺cells. These data reveal increased complexity within IFNγ-producing γδ T cells, comprising of immature and terminally differentiated subsets, that offer new insights into unconventional T cell biology.