Monocyte:T-cell interaction regulates human T-cell activation through a CD28/CD46 crosstalk.

T-cell activation requires engagement of the T-cell receptor and of at least one costimulatory molecule. The key role of CD28 in inducing T-cell activation was reported several decades ago and the molecular mechanisms involved have now been well described. The complement regulator CD46 also acts as a costimulatory molecule for T cells but, in contrast to CD28, has the ability to drive T-cell differentiation from producing some IFNγ to secreting some potent anti-inflammatory IL-10, acquiring a so-called Type I regulatory phenotype (Tr1). Proteolytic cleavage of CD46 occurs upon costimulation and is important for T-cell activation and IL-10 production. The observation that CD46 cleavage was reduced when PBMCs were costimulated compared with purified CD4(+) T cells led us to hypothesize that interactions between different cell types within the PBMCs were able to modulate the CD46 pathway. We show that CD46 downregulation is also reduced when CD4(+) T cells are cocultured with autologous monocytes. Indeed, monocyte: T-cell cocultures impaired CD46-mediated T-cell differentiation and coactivation, by reducing downregulation of surface CD46, lowering induction of the early activation marker CD69, as well as reducing the levels of IL-10 secretion. Blocking of CD86 could partly restore CD69 expression and cytokine secretion, demonstrating that the CD28: CD86 pathway regulates CD46 activation. Direct concomitant ligation of CD28 and CD46 on CD4(+) T cells also modulated CD46 expression and regulated cytokine production. These data identify a crosstalk between two main costimulatory pathways and provide novel insights into the regulation of human T-cell activation.