The Journal of Experimental Medicine
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Published online 28 June 2004 doi:10.1084/jem.20031234
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 1, 1-11
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Activation and Tolerance in CD4+ T Cells Reactive to an Immunoglobulin Variable Region

Christopher M. Snyder1, Katja Aviszus1, Ryan A. Heiser1, Daniel R. Tonkin1, Amanda M. Guth2, and Lawrence J. Wysocki1

1 Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado School of Medicine, Denver, CO 80206
2 Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523

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 {kappa} variable region peptide in monoclonal antibody (mAb) 36-71. The {kappa} 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 {kappa} chain of mAb 36-71, we found that {kappa}-specific T cells were centrally deleted in thymi of progeny that inherited the {kappa}Tg. Maternally derived {kappa}Tg antibody also induced central deletion. In marked contrast, adoptive transfer of TCR Tg T cells into {kappa}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{kappa} 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

The online version of this article contains supplemental material.

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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