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

• Published in: The EMBO journal Vol. 43; no. 14; pp. 2878 - 2907
• Main Authors: Wiesheu, Robert, Edwards, Sarah C, Hedley, Ann, Hall, Holly, Tosolini, Marie, Fares da Silva, Marcelo Gregorio Filho, Sumaria, Nital, Castenmiller, Suzanne M, Wardak, Leyma, Optaczy, Yasmin, Lynn, Amy, Hill, David G, Hayes, Alan J, Hay, Jodie, Kilbey, Anna, Shaw, Robin, Whyte, Declan, Walsh, Peter J, Michie, Alison M, Graham, Gerard J, Manoharan, Anand, Halsey, Christina, Blyth, Karen, Wolkers, Monika C, Miller, Crispin, Pennington, Daniel J, Jones, Gareth W, Fournie, Jean-Jacques, Bekiaris, Vasileios, Coffelt, Seth B
• Format: Journal Article
• Language: English
• Published: EMBO Press 30.05.2024
• Subjects: Life Sciences; γδ T Cells; Immunology; Innate Subject Categories Cancer; IL-27; Differentiation; Cancer
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/s44318-024-00133-1

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.