The Role of CD8 T-Cells in the Differentiation of TNF/iNOS-Producing Dendritic Cells and TH1 Responses

Abstract

In this study, we showed that activated human CD8 T-cells could induce DCs to produce IL-12p70 in vitro and this interaction also resulted in the production of a cytokine milieu that promoted the differentiation of monocytes into TNF/iNOS-producing (Tip) DCs. These Tip-DCs expressed high levels of MHC class II and upregulated co-stimulatory molecules CD40, CD80, CD86 and the classical DC maturation marker CD83. Tip-DCs exhibited T-cell priming ability and were capable of further driving Th1 responses, through their expression of TNF-alpha and iNOS, by priming naive CD4 T-cells for IFN-gamma production. Finally, we showed that the ability of CD8 T-cells to differentiate monocytes into Tip-DCs also occurred in an in vivo mouse model of allergic contact hypersensitivity (CHS). This differentiation and activation of Tip-DCs during CHS responses were observed to be compromised in beta2m-/-, IFN-gamma-/- and CCR2-/- mice and mice that were depleted of CD8, but not CD4, T-cells. In particular, the presence of Tip-DCs was significantly increased in mice that have been treated with a Th1-inducing topical sensitizer, DNCB, but not in mice that have been treated with a Th2-inducing sensitizer, TMA. Collectively, our results identify a role for CD8 T-cells in orchestrating Th1-mediating signals, not only through the rapid initiation of DC IL-12p70, but also through the differentiation of monocytes into Tip-DCs.