Pathophysiology underlying accelerated atherogenesis in renal disease: closing in on the target.

Abstract

Subsets of murine dendritic cells (DCs) from the spleen differ in their ability to induce proliferative responses in both primary and secondary CD4⁺ T cells. Recent evidence indicates that lymphoid-related CD8⁺ DCs fail to provide appropriate signals to freshly isolated secondary CD4⁺ T cells to sustain their proliferation in vitro. In the present study, we examined peptide-pulsed CD8⁻ and CD8⁺ DCs for ability to stimulate Th1 and Th2 cell clones with the same Ag specificity. Defective ability to induce proliferation was selectively shown by CD8⁺ DCs presenting Ag to the Th1 clone. The deficiency in CD8⁺ DCs was overcome by CD40 triggering before peptide pulsing. When exposed to CD8⁺ DCs in the absence of CD40 activation, the Th1 clone expressed low levels of CD40 ligand and high levels of surface CTLA-4. Neutralization of CTLA-4 during the DC/T cell coculture resulted in increased CD40 ligand expression and proliferation of T cells. Remarkably, the activation of CD40 on DCs under conditions that would increase Th1 cell proliferation, also resulted in down-regulation of surface CTLA-4. These results confirm differential effects of CD8⁺ and CD8⁻ DCs in the stimulation of Ag-primed Th cells. In addition, they suggest that reciprocal regulation of CD40 ligand and CTLA-4 expression occurs in Th1 cells exposed to CD8⁺ DCs.