T cell recognition and tolerance of antibody diversity.
The capacity of B cells to self-present their Ab variable regions in the context of class II MHC structures suggests a potential regulatory problem. If T cells were able to recognize self-presented Ab, then T cell help might be delivered to B cells independently of a foreign carrier epitope, resulting in a chronic state of unregulated Ab synthesis. For this reason, we have proposed that T cells normally attain a state of tolerance to Ab V region diversity. Here, we tested this idea by performing direct immunizations with unmutated isologous mAb. We also identified and analyzed epitopes recognized by class II MHC-restricted T cell hybridomas that were originally generated against two physiologically mutated isologous mAb. Our results indicate that the class II MHC-restricted T cell repertoire is tolerant of germ-line-encoded Ab diversity and that the physiologic somatic hypermutation process creates immunogenic epitopes in Ab V regions, in some cases by producing class II MHC-binding peptides. In agreement with these findings, we found that germ-line-encoded Ab V regions are presented by endogenous splenic APC at a level that is physiologically significant.
Eyerman
M C
MC
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA.
Zhang
X
X
Wysocki
L J
LJ
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000916:Antibody Diversity; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance; D051379:Mice; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*; D010132:p-Azobenzenearsonate
D000911:Antibodies, Monoclonal; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010132:p-Azobenzenearsonate