B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen

Abstract

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 D(k), showed remarkably low, but detectable, affinity to 3-83. The 3-83 antibody bound Kb with K(A) ~2 x 105 M-1 and bound 10-fold more weakly to the Kbm3 (K(A)~2 x 104 M-1) and D(k) antigens. Breeding 3-83 immunoglobulin transgenic mice with mice expressing these ultralow affinity Kbm3 and D(k) 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 λ 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, K(k), 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.