Signature cytokine-associated transcriptome analysis of effector γδ T cells identifies subset-specific regulators of peripheral activation
Daniel Inácio, Tiago Amado, Ana Pamplona, Daniel Sobral, Carolina Cunha, Rita F. Santos, Liliana Oliveira, Nelly Rouquié, Alexandre M. Carmo, Renaud Lesourne, Anita Quintal Gomes, Bruno Silva‐Santos
Abstract
γδ 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. Here, the authors use a double-reporter system to tag IFNγ-producing versus IL-17A-producing γδ T cells to compile a trancriptomic resource of these cell subsets in mice at steady state and in response to cerebral malaria or multiple sclerosis.