Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8+ T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing islet-specific regulatory CD4+ T cells may offer a tissue-specific intervention therapy. The effect of Combi-DCs on CD8+ T cells, however, remains unknown. To investigate the interaction of CD8+ T cells with Combi-DCs presenting epitopes on HLA class I, naive, and memory CD8+ T cells were co-cultured with DCs and proliferation and function of peptide-specific T cells were analyzed. Antigen-loaded Combi-DCs were unable to prime naïve CD8+ T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8+ T cells that had been primed by mature monocyte-derived DCs (moDCs) was curtailed by Combi-DCs in co-cultures. Combi-DCs expanded memory T cells once, but CD8+ T-cell numbers collapsed by subsequent re-stimulation with Combi-DCs. Our data point that (re)activation of CD8+ T cells by antigen-pulsed Combi-DCs does not promote, but rather deteriorates, CD8+ T-cell immunity. Yet, Combi-DCs pulsed with CD8+ T-cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi-DCs infused into patients in therapeutic immune intervention strategies.