Abstract
Systemic Lupus Erythematosus (SLE) is characterized by pathogenic autoantibodies against nucleic acid-containing antigens. Understanding which B-cell subsets give rise to these autoantibodies may reveal therapeutic approaches for SLE that spare protective responses. Mice lacking the tyrosine kinase Lyn, which limits B and myeloid cell activation, develop lupus-like autoimmune diseases characterized by increased autoreactive plasma cells (PCs). We used a fate-mapping strategy to determine the contribution of T-bet(+) B cells, a subset thought to be pathogenic in lupus, to the accumulation of PCs and autoantibodies in Lyn(-/-) mice. Approximately, 50% of splenic PCs in Lyn(-/-) mice originated from T-bet(+) cells, a significant increase compared to WT mice. In vitro, splenic PCs derived from T-bet(+) B cells secreted both IgM and IgG anti-dsDNA antibodies. To determine the role of these cells in autoantibody production in vivo, we prevented T-bet(+) B cells from differentiating into PCs or class switching in Lyn(-/-) mice. This resulted in a partial reduction in splenic PCs and anti-dsDNA IgM and complete abrogation of anti-dsDNA IgG. Thus, T-bet(+) B cells make an important contribution to the autoreactive PC pool in Lyn(-/-) mice.