The first demonstration in vivo that HFE acts as a negative regulator of CD8+ T-lymphocyte activation and differentiation was provided with the study by Costa et al. [32] of lymphocyte gene expression signatures from HFE-related hemochromatosis patients and mouse models, where it was shown that the lack of HFE impacts on several activation markers in CD8+ T lymphocytes [32]. This evidence concerns the gene CD8A and hemochromatosis.