Legend or Truth: Mature CD4⁺CD8⁺ Double-Positive T Cells in the Periphery in Health and Disease

The expression of CD4 and CD8 co-receptors defines two distinct T cell populations with specialized functions. While CD4⁺ T cells support and modulate immune responses through different T-helper (Th) and regulatory subtypes, CD8⁺ T cells eliminate cells that might threaten the organism, for example, virus-infected or tumor cells. However, a paradoxical population of CD4⁺CD8⁺ double-positive (DP) T cells challenging this paradigm has been found in the peripheral blood. This subset has been observed in healthy as well as pathological conditions, suggesting unique and well-defined functions. Furthermore, DP T cells express activation markers and exhibit memory-like features, displaying an effector memory (EM) and central memory (CM) phenotype. A subset expressing high CD4 (CD4^bright+) and intermediate CD8 (CD8^dim+) levels and a population of CD8^bright+CD4^dim+ T cells have been identified within DP T cells, suggesting that this small subpopulation may be heterogeneous. This review summarizes the current literature on DP T cells in humans in health and diseases. In addition, we point out that strategies to better characterize this minor T cell subset's role in regulating immune responses are necessary.