Vaccination with Flt3L-induced CD8α+ dendritic cells prevents CD4+ T helper cell-mediated experimental autoimmune myocarditis

Experimental autoimmune myocarditis (EAM) represents a CD4(+) T helper (Th) cell-mediated mouse model of inflammatory heart disease. Interferon (IFN)-gamma, typically produced by Th1 cells, reduces EAM severity in myosin heavy-chain-(MyHC)-alpha peptide/Complete Freund adjuvant-immunized mice. Thus, developing a vaccination strategy that promotes differentiation of Th1 cells may be beneficial in EAM. FMS-like tyrosine kinase 3 ligand (Flt3L)-induced splenic CD8 alpha(+) dendritic cells (DC), which produce interleukin (IL)-12p35, were identified to selectively induce biased differentiation towards Th1. Mice vaccinated with MyHC-alpha-loaded Flt3L-induced splenic CD8 alpha(+) DC were protected from EAM. In contrast, when Flt3L-induced splenic CD8 alpha(+) DC were pre-stimulated and over-activated with LPS and alpha CD40 antibodies or loaded with unspecific OVA(323-339) peptide instead of MyHC-alpha peptide, mice developed similar disease scores as non-vaccinated controls. Vaccination efficacy depended on IFN-gamma, since CD8 alpha(+)-vaccinated IFN-gamma R-/- mice were not protected. Importantly, splenic CD8 alpha(+) vaccination was independent of regulatory T cells. Taken together, Flt3L-induced dendritic cell-based antigen-specific vaccination limits expansion of auto-reactive Th cells and protects mice from autoimmune heart inflammation. (C) 2013 Elsevier Ltd. All rights reserved.