Effects of IFN‐α as a signal‐3 cytokine on human naïve and antigen‐experienced CD8⁺ T cells

IFN‐α/β link innate and adaptive immune responses by directly acting on naïve CD8⁺ T cells. This concept unveiled in mice remains unexplored in humans. To investigate that, human CD8⁺CD45RO⁻ cells were stimulated with beads coated with anti‐CD3 and anti‐CD28 mAb, mimicking Ag (type‐1) and co‐stimulatory (type‐2) signals, in the presence or absence of IFN‐α and their transcriptional profiles were defined by cDNA‐microarrays. We show that IFN‐α provides a strong third signal directly to human CD8⁺ T cells resulting in regulation of critical genes for their overall activation. This transcriptional effect was substantiated at the protein level and verified by functional assays. Interestingly, the biological effects derived from this stimulation vary depending on the CD8⁺ T‐cell population. Thus, whereas IFN‐α increases the proliferative capacity of naïve CD8⁺ T cells, it inhibits or does not affect the proliferation of Ag‐experienced cells, such as memory and effector CTL, including CMV‐specific lymphocytes. Cytolysis and IFN‐γ‐secretion of all these populations are enhanced by IFN‐α‐derived signals, which are critical in naïve CD8⁺ T cells for acquisition of effector functions. Our findings in human CD8⁺ T cells are informative to understand and improve IFN‐α‐based therapies for viral and malignant diseases.