B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen.
To assess the sensitivity of B cell tolerance with respect to receptor/autoantigen affinity, we identified low affinity ligands to the 3-83 (anti-major histocompatibility complex class I) antibody and tested the ability of these ligands to induce central and peripheral tolerance in 3-83 transgenic mice. Several class I protein alloforms, including Kbm3 and Dk, showed remarkably low, but detectable, affinity to 3-83. The 3-83 antibody bound Kb with K lambda approximately 2 x 10(5) M-1 and bound 10-fold more weakly to the Kbm3 (K lambda approximately 2 x 10(4) M-1) and Dk antigens. Breeding 3-83 immunoglobulin transgenic mice with mice expressing these ultralow affinity Kbm3 and Dk ligands resulted in virtually complete deletion of the autoreactive B cells from the peripheral lymphoid tissues. These low affinity antigens also induced receptor editing, as measured by elevated RAG mRNA levels in the bone marrow and excess levels of id- variant B cells bearing lambda light chains in the spleen. Reactive class I antigens were also able to mediate deletion of mature B cells when injected into the peritoneal cavity of 3-83 transgenic mice. Although the highest affinity ligand, Kk, was consistently able to induce elimination of the 3-83 peritoneal B cells, the lower affinity ligands were only partially effective. These results demonstrate the remarkable sensitivity of the deletion and receptor-editing mechanisms in immature B cells, and may suggest a higher affinity threshold for deletion of peripheral, mature B cells.
Lang
J
J
Department of Immunology, University of Colorado Health Sciences Center, Denver 80220, USA.
Jackson
M
M
Teyton
L
L
Brunmark
A
A
Kane
K
K
Nemazee
D
D
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D017637:Clonal Deletion; D003429:Cross Reactions; D006183:H-2 Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007130:Immunoglobulin Idiotypes; D008024:Ligands; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D010537:Peritoneum / Q000166:cytology / Q000276:immunology; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000235:genetics*
D001324:Autoantigens; D006183:H-2 Antigens; C024755:H-2K(K) antigen; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; D007130:Immunoglobulin Idiotypes; D008024:Ligands; D011947:Receptors, Antigen, B-Cell