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International audience; Peripheral CD4 + CD8 + double positive (DP) T cells are a phenotypically and functionally heterogeneous population depending on their origin and pathologic context. We previously identified among tumour infiltrating lymphocytes in melanoma, a tumour-reactive MHC class-I restricted CD4 low CD8 high DP αβ T-cell subpopulation with CD4-like function. In this study, we used an in-depth comparative transriptomic analysis of intra-melanoma DP T cells and CD4 and CD8 single positive (SP) T cells, to better comprehend the origin of this DP phenotype, and define the transcriptomic signature of activated DP T cells. We observed that intra-melanoma DP T cells were transcriptome-wise closer to their CD8 SP T-cell counterparts in terms of number of genes differentially expressed (97 in common with CD8 SP T cells and 15 with CD4 SP T cells) but presented hallmarks of a transition to a CD4-like functional profile (CD40LG) with a decreased cytotoxic signature (KLRC1) in favour of an increased cytokine-receptor interaction signature (IL4, IL24, IL17A…). This unleashed CD4-like program could be the results of the observed unbalanced expression of the THPOK/Runx3 transcription factors in DP T cells. Overall, this study allow us to speculate that intra-melanoma DP T cells arise from CD8 SP T cells being reprogrammed to a helper function. Contrary to the CD4 + CD8 + double positive (DP) thymocytes, well described as a T cell development stage, peripheral DP αβ T cells had attracted less attention mostly because of their weak frequency in the peripheral blood of healthy human donors (1 to 3%) 1,2. Nonetheless, following diverse inflammatory processes from viral or parasitic infections 3-5 , to autoimmune diseases 6,7 or cancer 8-14 , this subpopulation can become quite predominant in the blood or in the inflamed tissue/organ. This suggests a causal relationship between DP T cell emergence and disease. From these studies, DP T cells appeared as a more heterogeneous population than initially thought. Based on the co-expression level of the CD8 and CD4 co-receptors, peripheral DP T cells can be subdivided into three major subtypes: (i) the CD4 high CD8 low phenotype expressing the CD8αα homodimer, (ii) the CD4 high CD8 high phenotype and (iii) the CD4 low CD8 high phenotype both expressing the CD8αβ heterodimer 15,16. Although not always clearly demonstrated, these diverse phenotypes are presumably resulting from diverse origins. Thus, it has been proposed that CD4 high CD8 low DP T cells derive from peripheral CD4 T cells that following activation with the appropriate co-stimuli such as IL-4, TGF-β or retinoic acid can induce the CD8αα co-receptor expression at a low level 17. On the other hand, the CD4 low CD8 high phenotype is considered to be emerging from peripheral CD8 T cells that after activation with strong stimuli can reexpress the CD4 co-receptor at a low level 18,19. Regarding the CD4 high CD8 high phenotype, less is known and either a thymus or a peripheral origin can be considered. In our previous work, we have described the enrichment in the tumour infiltrate of several solid cancers including melanoma, of a class-I-restricted DP T-cell population presenting the CD4 low CD8 high phenotype 9,10. This population was not increased in the peripheral blood suggesting the influence of the tumour microenviron-ment upon the development of DP T cells. Because of their class-I restriction and their CD4 low CD8 high phenotype