Tolerance and immunity to the inducible self antigen C-reactive protein in transgenic mice.
The understanding of immunological tolerance has been greatly aided by the development of transgenic animal models in which expression of a specific T cell receptor (or B cell receptor) and its cognate self antigen is experimentally controlled. In most cases, expression of the self antigen was constitutive and did not allow for variation of its time- and dose-dependent expression pattern, parameters which are known to influence the balance of tolerance versus immunity. We describe a transgenic model in which expression of human C-reactive protein (hCRP), an acute-phase protein, is tightly controlled at basal levels (female mice express around 10(-9) M and male mice 5 x 10(-7) M circulating hCRP) and is highly inducible (induction factor of 25-500). T cells from C57BL/6 mice recognize two epitopes of hCRP termed A (residues 79-95) and B (residues 87-102). Different efficacies of presentation in vitro and in vivo identify epitope A as sub-dominant and epitope B as dominant. T cells of non-induced hCRP transgenic mice are tolerant to the dominant epitope, but reactive to the subdominant epitope. A hCRP-specific IgG antibody response is detectable in transgenic mice, but is weaker than in littermates. Upon induction of hCRP, both T cell epitopes are presented by thymic and splenic antigen-presenting cells (APC) in vivo. Kinetics of presentation by splenic APC closely match serum kinetics of hCRP, whereas presentation in the thymus is considerably prolonged. This model enables epitope-specific T cell tolerance to be studied as a function of time- and dose-dependent expression of the self antigen.
Klein
T C
TC
Tumor Immunology Programme, German Cancer Research Centre, Heidelberg, Germany.
Döffinger
R
R
Pepys
M B
MB
Rüther
U
U
Kyewski
B
B
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology; D002097:C-Reactive Protein / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology
D000939:Epitopes; D002097:C-Reactive Protein