Inácio, DanielAmado, TiagoPamplona, AnaSobral, DanielCunha, CarolinaSantos, Rita F.Oliveira, LilianaRouquié, NellyCarmo, Alexandre M.Lesourne, RenaudGomes, Anita Q.Santos, Bruno SilvaSantos, Ana Rita2026-01-142026-01-142025-01-29Inácio, D., Amado, T., Pamplona, A., Sobral, D., Cunha, C., Santos, R. F., Oliveira, L., Rouquié, N., Carmo, A. M., Lesourne, R., Gomes, A. Q., & Silva-Santos, B. (2025). Signature cytokine-associated transcriptome analysis of effector γδ T cells identifies subset-specific regulators of peripheral activation. Nature Immunology, 26(3), 497–510. https://doi.org/10.1038/s41590-024-02073-8http://hdl.handle.net/10400.22/31514γδ T cells producing either interleukin-17A (γδ17 cells) or interferon-γ (γδIFN cells) are generated in the mouse thymus, but the molecular regulators of their peripheral functions are not fully characterized. Here we established an Il17a-GFP:Ifng-YFP double-reporter mouse strain to analyze at unprecedented depth the transcriptomes of pure γδ17 cell versus γδIFN cell populations from peripheral lymph nodes. Within a very high fraction of differentially expressed genes, we identify a panel of 20 new signature genes in steady-state γδ17 cells versus γδIFN cells, which we further validate in models of experimental autoimmune encephalomyelitis and cerebral malaria, respectively. Among the signature genes, we show that the co-receptor CD6 and the signaling protein Themis promote the activation and proliferation of peripheral γδIFN cells in response to T cell antigen receptor stimulation in vitro and to Plasmodium infection in vivo. This resource can help to understand the distinct activities of effector γδ T cell subsets in pathophysiology.engγδ T cellsinterleukin-17A (γδ17 cells)interferon-γ (γδIFN cells)research article10.1038/s41590-024-02073-81529-2908