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)-γ, typically produced by Th1 cells, reduces EAM severity in myosin heavy-chain-(MyHC)-α 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 CD8α(+) dendritic cells (DC), which produce interleukin (IL)-12p35, were identified to selectively induce biased differentiation towards Th1. Mice vaccinated with MyHC-α-loaded Flt3L-induced splenic CD8α(+) DC were protected from EAM. In contrast, when Flt3L-induced splenic CD8α(+) DC were pre-stimulated and over-activated with LPS and αCD40 antibodies or loaded with unspecific OVA(323-339) peptide instead of MyHC-α peptide, mice developed similar disease scores as non-vaccinated controls. Vaccination efficacy depended on IFN-γ, since CD8α(+)-vaccinated IFN-γR(-/-) mice were not protected. Importantly, splenic CD8α(+) 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.
Division of Cardioimmunology, Cardiovascular Research, Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, Switzerland; Division of Cardiology, Heart and Stroke/Richard Lewar Centre of Excellence, Toronto General Research Institute, University Health Network, University of Toronto, Ontario, Canada. Electronic address: alan.valaperti@me.com.
Alan
A
Valaperti
Mototsugu
M
Nishii
Davide
D
Germano
Peter P
PP
Liu
Urs
U
Eriksson
D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009205:Myocarditis / Q000517:prevention & control*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014611:Vaccination / Q000379:methods*
D008565:Membrane Proteins; C084881:flt3 ligand protein; D007371:Interferon-gamma
Autoimmunity; CD4(+) T helper; Dendritic cells; EAM; FMS-like tyrosine kinase 3 ligand; Flt3L; MyHC; Myocarditis; Th; Th1; Th17; experimental autoimmune myocarditis; myosin heavy-chain