We have previously demonstrated that IT9302, a nonameric peptide homologous to the C-terminal domain of human IL-10, mimics several effects of the cytokine including down-regulation of the antigen presentation machinery and increased sensitivity of tumor cells to NK-mediated lysis. In the present report, we have explored a potential therapeutic utility for IT9302 related to the ex vivo production of tolerogenic dendritic cells (DCs). Our results indicate that IT9302 impedes human monocyte response to differentiation factors and reduces antigen presentation and co-stimulatory capacity by DCs. Additionally, peptide-treated DCs show impaired capacity to stimulate T-cell proliferation and IFN-γ production. IT9302 exerts its effect through mechanisms, in part, distinct from IL-10, involving STAT3 inactivation and NF-κB intracellular pathway. IT9302-treated DCs display increased expression of membrane-associated TGF-β, linked to a more effective induction of foxp3+ regulatory T cells. These results illustrate for the first time that a short synthetic peptide can promote monocytes differentiation to tolerogenic DCs with therapeutic potential for the treatment of autoimmune and transplantation-related immunopathologic disease.
Bibliographical noteFunding Information:
This work was supported by grants from the National Fund for Scientific and Technological Development (FONDECYT 1090238 and 1090243 ), the Fund for the Promotion of Scientific and Technological Development (FONDEF DO5I10366 ), the Millennium Nucleus of Immunology and Immunotherapy ( P04/030-F ), the Research Support Office, Clinical Hospital of the University of Chile (OAIC) and Rolf Kiessling's grants from the Swedish Cancer Society , Cancer Society of Stockholm , and the Stockholm City Council (ALF-grant).
- Antigen presentation
- Dendritic cells
- MHC class I
- Regulatory T cells