ABSTRACT
Myocarditis can develop into inflammatory cardiomyopathy through chronic stimulation of myosin heavy chain 6-specific T helper (TH)1 and TH17 cells. However, mechanisms governing the cardiotoxicity programming of heart-specific T cells have remained elusive. Using a mouse model of spontaneous autoimmune myocarditis, we show that progression of myocarditis to lethal heart disease depends on cardiac myosin-specific TH17 cells imprinted in the intestine by a commensal Bacteroides species peptide mimic. Both the successful prevention of lethal disease in mice by antibiotic therapy and the significantly elevated Bacteroides-specific CD4+ T cell and B cell responses observed in human myocarditis patients suggest that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible individuals. The ability to restrain cardiotoxic T cells through manipulation of the microbiome thereby transforms inflammatory cardiomyopathy into a targetable disease.
Subject(s)
Autoimmune Diseases/complications , Bacteroides/immunology , Cardiomyopathy, Dilated/immunology , Cardiomyopathy, Dilated/microbiology , Gastrointestinal Microbiome/immunology , Myocarditis/complications , Peptides/immunology , beta-Galactosidase/immunology , Animals , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Disease Models, Animal , Humans , Intestines/microbiology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Myocarditis/immunology , Myosin Heavy Chains/genetics , Myosin Heavy Chains/immunology , Th17 Cells/immunologyABSTRACT
Toll-like receptors (TLR) recognize microbial and viral patterns and activate dendritic cells (DC). TLR distribution among human DC subsets is heterogeneous: plasmacytoid DC (PDC) express TLR1, 7 and 9, while other DC types do not express TLR9 but express other TLR. Here, we report that mRNA for most TLR is expressed at similar levels by murine splenic DC sub-types, including PDC, but that TLR3 is preferentially expressed by CD8 alpha(+) DC while TLR5 and TLR7 are selectively absent from the same subset. Consistent with the latter, TLR7 ligand activates CD8 alpha(-) DC and PDC, but not CD8 alpha(+) DC as measured by survival ex vivo, up-regulation of surface markers and production of IL-12p40. These data suggest that the dichotomy in TLR expression between plasmacytoid and non-plasmacytoid DC is not conserved between species. However, lack of TLR7 expression could restrict the involvement of CD8 alpha(+) DC in recognition of certain mouse pathogens.
