Tolerance and immunity to the inducible self antigen C-reactive protein in transgenic mice

• Published in: European journal of immunology Vol. 25; no. 12; p. 3489
• Main Authors: Klein, T C, Döffinger, R, Pepys, M B, Rüther, U, Kyewski, B
• Format: Journal Article
• Language: English
• Published: Germany 01.12.1995
• Subjects: Amino Acid Sequence; Animals; Antigen Presentation; B-Lymphocytes - immunology; C-Reactive Protein - biosynthesis; C-Reactive Protein - genetics; C-Reactive Protein - immunology; Epitopes - immunology; Female; Humans; Immune Tolerance; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; T-Lymphocytes - immunology
• ISSN: 0014-2980
• DOI: 10.1002/eji.1830251242

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.