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Address correspondence to Lawrence J. Wysocki, Integrated Dept. of Immunology, K902a, National Jewish Medical and Research Center and University of Colorado School of Medicine, 1400 Jackson St., Denver, CO 80206. Phone: (303) 398-1385; Fax: (303) 270-2182; email: wysockiL{at}njc.org
Antibody diversity creates an immunoregulatory challenge for T cells that must cooperate with B cells, yet discriminate between self and nonself. To examine the consequences of T cell reactions to the B cell receptor (BCR), we generated a transgenic (Tg) line of mice expressing a T cell receptor (TCR) specific for a
variable region peptide in monoclonal antibody (mAb) 36-71. The epitope was originally generated by a pair of somatic mutations that arose naturally during an immune response. By crossing this TCR Tg mouse with mice expressing the chain of mAb 36-71, we found that -specific T cells were centrally deleted in thymi of progeny that inherited the Tg. Maternally derived Tg antibody also induced central deletion. In marked contrast, adoptive transfer of TCR Tg T cells into Tg recipients resulted in T and B cell activation, lymphadenopathy, splenomegaly, and the production of IgG antichromatin antibodies by day 14. In most recipients, autoantibody levels increased with time, Tg T cells persisted for months, and a state of lupus nephritis developed. Despite this, Tg T cells appeared to be tolerant as assessed by severely diminished proliferative responses to the V peptide. These results reveal the importance of attaining central and peripheral T cell tolerance to BCR V regions. They suggest that nondeletional forms of T tolerance in BCR-reactive T cells may be insufficient to preclude helper activity for chromatin-reactive B cells.
Key Words: lymphocytes • SLE • antinuclear antibody • self-tolerance • glomerulonephritis
Abbreviations used in this paper: BCR, B cell receptor; CFSE, carboxyfluorescein diacetate succinimidyl ester; FR1, framework-1; GVH, graft-versus-host; H&E, hematoxylin and eosin; RT, room temperature; Tg, transgenic.
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