Peripheral Tolerance in Anti-Insulin B Lymphocytes

Abstract

Overall, these studies examine how peripheral tolerance is governed for autoreactive B lymphocytes that bind the relevant autoAg, insulin. CSR-competent anti-insulin B cells enter mature compartments but are anergic, demonstrated by impaired proliferation to stimulation by a panel of B cell mitogens in vitro and total lack of IgG anti-insulin antibody production following TD immunization of VH125SD B6 mice. Reversal of anti-insulin B cell anergy is demonstrated by proliferation to insulin plus LPS in vitro and IgG2a antibody production following immunization of VH125SD mice with insulin conjugated to a type 1 TI antigen. This combined BCR/TLR co-stimulation effect in vivo is accompanied by entry of insulin-binding B cells into GCs, in contrast to expectations that such TI-mediated responses would arise in extrafollicular sites. In GCs, anti-insulin L chains are not discarded but rather selected from the pre-immune repertoire. These studies reveal a new pathway to drive loss of tolerance for CSR-competent anti-insulin B cells.