CD11b⁺ monocytes abrogate Th17 CD4⁺ T cell-mediated experimental autoimmune myocarditis

Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mouse model of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease, peaking 21 days after α-myosin H chain peptide (MyHC-α)/CFA immunization and largely resolving thereafter. In IFN-γR^-/- mice, however, EAM is exacerbated and shows a chronic progressive disease course. We found that this progressive disease course paralleled persistently elevated IL-17 release from T cells infiltrating the hearts of IFN-γR^-/- mice 30 days after immunization. In fact, IL-17 promoted the recruitment of CD11b⁺ monocytes, the major heart-infiltrating cells in EAM. In turn, CD11b⁺ monocytes suppressed MyHC-α-specific Th17 T cell responses IFN-γ-dependently in vitro. In vivo, injection of IFN-γR^-/-CD11b⁺, but not IFN-γR^-/-CD11b⁺, monocytes, suppressed MyHC-γ-specific T cells, and abrogated the progressive disease course in IFN-γR^-/- mice. Finally, coinjection of MyHC-α-specific, but not OVA-transgenic, IFN-γ-releasing CD4⁺ Th1 T cell lines, together with MyHC-α-specific Th17 T cells protected RAG2^-/- mice from EAM. In conclusion, CD11b⁺ monocytes play a dual role in EAM: as a major cellular substrate of IL-17-induced inflammation and as mediators of an IFN-γ-dependent negative feedback loop confining disease progression.