CD46 is a potent co-stimulatory receptor for expansion of human IFN-γ-producing CD8+ T cells

•Activation of CD46 induces rapid down-modulation of CD46 expression on the surface of CD8+ T cells.•CD46 co-stimulation potently induces CD8+ T cell proliferation.•CD46 co-stimulation does not induce a switch to IL-10 production in CD8+ T cells, as is known for CD4+ T cells.•CD46 co-stimulation predominantly expands IFN-γ-producing CD8+ T cells. Similar to CD4+ T cells, precursor CD8+ T cells are thought to depend on a co-stimulatory signal through CD28 for proliferation and differentiation into effector cells. CD46 is another co-stimulatory receptor that promotes differentiation of CD4+ T-helper cells type 1 (Th1 cells) into a regulatory phenotype with a switch from IFN-γ towards IL-10-secretion over time. Whether CD46 exerts a similar function on CD8+ T cells remains to be fully elucidated. Here, we demonstrate that CD46 co-stimulation induced secretion of IFN-γ as well as expansion of IFN-γ-secreting CD8+ T cells. In contrast to CD46 co-stimulation of CD4+ T cells, CD8+ T cells did not differentiate into a regulatory IL-10-secreting phenotype. This demonstrates that CD46 is a co-stimulatory receptor on CD8+ T cells, and that it exerts separate functions during CD4+ and CD8+ T-cell differentiation.