Activation of dendritic cells through the interleukin 1 receptor 1 is critical for the induction of autoimmune myocarditis.
Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1-deficient (IL-1R1(-/-)) mice are protected from development of autoimmune myocarditis after immunization with alpha-myosin-peptide(614-629). CD4(+) T cells from immunized IL-1R1(-/-) mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1(-/-)CD4(+) T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1(-/-) mice. Accordingly, production of tumor necrosis factor (TNF)-alpha, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1(+/+) but not IL-1R1(-/-) dendritic cells into IL-1R1(-/-) mice fully restored disease susceptibility by rendering IL-1R1(-/-) CD4(+) T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4(+) T cells and autoimmunity.
Eriksson
Urs
U
Medicine A, University Hospital, CH-4031 Basel, Switzerland. ueriksson@uhbs.ch
Kurrer
Michael O
MO
Sonderegger
Ivo
I
Iezzi
Giandomenica
G
Tafuri
Anna
A
Hunziker
Lukas
L
Suzuki
Shinobu
S
Bachmaier
Kurt
K
Bingisser
Roland M
RM
Penninger
Josef M
JM
Kopf
Manfred
M
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009205:Myocarditis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I; D024723:Ventricular Myosins / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D010446:Peptide Fragments; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D024723:Ventricular Myosins