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Positive Selection of Anti–Thy-1 Autoreactive B-1 Cells and Natural Serum Autoantibody Production Independent from Bone Marrow B Cell Development

Kyoko Hayakawa, Masanao Asano, Susan A. Shinton, Ming Gui, Li-Jun Wen, Joni Dashoff and Richard R. Hardy

Fox Chase Cancer Center, Philadelphia, PA 19111

Address correspondence to Kyoko Hayakawa, Fox Chase Cancer Center, Reimann Building, 7701 Burholme Avenue, Philadelphia, PA 19111. Phone: 215-728-5362; Fax: 215-728-3574; E-mail: K_Hayakawa{at}fccc.edu

A natural serum autoantibody specific for the Thy-1 glycoprotein (anti–Thy-1 autoantibody [ATA]) is produced by B-1 cells that are positively selected by self-antigen. Here, using ATAµ transgenic mice we show that cells with this B cell receptor are negatively selected during bone marrow (BM) development. In a Thy-1 null environment, BM ATA B cells progress to a normal follicular stage in spleen. However, in a self-antigen–positive environment, development is arrested at an immature stage in the spleen, concomitant with induction of CD5. Such cells are tolerant and short-lived, different from B-1. Nonetheless, ATA-positive selection was evident by self-antigen–dependent high serum ATA production, comprising 90% of serum immunoglobulin M in ATAµ mice. Splenectomy did not eliminate ATA production and transfer of tolerant splenic B cells did not induce it. These findings demonstrate that B-1 positive selection, resulting in the production of natural serum ATA, arises independently from the major pathway of BM B cell development and selection.

Key Words: B-1 • ATA • CD5 • IgM • Thy-1

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