An immunoglobulin C kappa-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system.
Understanding immune tolerance mechanisms is a major goal of immunology research, but mechanistic studies have generally required the use of mouse models carrying untargeted or targeted antigen receptor transgenes, which distort lymphocyte development and therefore preclude analysis of a truly normal immune system. Here we demonstrate an advance in in vivo analysis of immune tolerance that overcomes these shortcomings. We show that custom superantigens generated by single chain antibody technology permit the study of tolerance in a normal, polyclonal immune system. In the present study we generated a membrane-tethered anti-Igkappa-reactive single chain antibody chimeric gene and expressed it as a transgene in mice. B cell tolerance was directly characterized in the transgenic mice and in radiation bone marrow chimeras in which ligand-bearing mice served as recipients of nontransgenic cells. We find that the ubiquitously expressed, Igkappa-reactive ligand induces efficient B cell tolerance primarily or exclusively by receptor editing. We also demonstrate the unique advantages of our model in the genetic and cellular analysis of immune tolerance.
Ait-Azzouzene
Djemel
D
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Verkoczy
Laurent
L
Peters
Jorieke
J
Gavin
Amanda
A
Skog
Patrick
P
Vela
José Luis
JL
Nemazee
David
D
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D016654:Genes, RAG-1 / Q000235:genetics; D007107:Immune System / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics* / Q000276:immunology*; D007146:Immunoglobulin lambda-Chains / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology
D001324:Autoantigens; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins
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