Inácio, DanielAmado, TiagoPamplona, AnaSobral, DanielCunha, CarolinaSantos, Rita F.Oliveira, LilianaRouquié, NellyCarmo, Alexandre M.Lesourne, RenaudGomes, Anita Q.Silva-Santos, Bruno2025-11-142025-11-142025-01-29Nat Immunol. 2025 Mar;26(3):497-510. doi: 10.1038/s41590-024-02073-8. Epub 2025 Jan 291529-2908http://hdl.handle.net/10400.18/10613γδ T cells producing either interleukin-17A (γδ cells) or interferon-γ (γδ 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 γδ cell versus γδ 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 γδ cells versus γδ 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 γδ 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 cellsTranscriptome AnalysisCytokinesSubset-Specific RegulatorsPeripheral ActivationGeneticsImmunologyjournal article10.1038/s41590-024-02073-81529-291639881001