Induction of autoimmunity in the absence of CD28 costimulation.
Ag-specific activation of T lymphocytes requires two signals, one by the TCR and a second by costimulatory molecules. In a CD4+ T helper cell-dependent experimental autoimmune myocarditis model, we provide genetic evidence that cardiac myosin-induced autoimmune myocarditis and the production of IgG auto-Abs is dependent on functional T cells and did not occur in mice lacking the tyrosine kinase p56lck or the tyrosine phosphatase CD45. By contrast, animals lacking the T cell-costimulatory molecule CD28 (CD28 -/-) developed autoimmune heart disease, although at significantly lower severity than in heterozygous littermates, and produced IgG auto-Abs depending on the concentration of the autoantigen administered. In addition, the isotypes of IgG auto-Abs specific for cardiac myosin differed between CD28 +/- and CD28 -/- mice. Whereas CD28 +/- mice predominantly produced Th2-mediated IgG1 auto-Abs, CD28 -/- mice produced predominantly IgG2a. These data suggest that CD28 costimulation plays a crucial role in induction and maintenance of autoimmune heart disease and that CD28 expression is required for predominant Th2-IgG1 responses in an autoimmune setting.
Bachmaier
K
K
Amgen Institute, Ontario Cancer Institute, Toronto, Canada.
Pummerer
C
C
Shahinian
A
A
Ionescu
J
J
Neu
N
N
Mak
T W
TW
Penninger
J M
JM
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology*; D018106:CD28 Antigens / Q000502:physiology*; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000502:physiology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000209:etiology*; D009218:Myosins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*; D019061:src-Family Kinases / Q000172:deficiency
D001323:Autoantibodies; D001324:Autoantigens; D018106:CD28 Antigens; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D017493:Leukocyte Common Antigens; D009218:Myosins