Activation and tolerance in CD4(+) T cells reactive to an immunoglobulin variable region.
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 kappaTg. Maternally derived kappaTg antibody also induced central deletion. In marked contrast, adoptive transfer of TCR Tg T cells into kappaTg 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 Vkappa 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.
Snyder
Christopher M
CM
Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado School of Medicine, 1400 Jackson St., Denver, CO 80206, USA.
Aviszus
Katja
K
Heiser
Ryan A
RA
Tonkin
Daniel R
DR
Guth
Amanda M
AM
Wysocki
Lawrence J
LJ
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D011948:Receptors, Antigen, T-Cell