Transgenic rearranged T cell receptor gene inhibits lymphadenopathy and accumulation of CD4-CD8-B220+ T cells in lpr/lpr mice.
The lpr gene in homozygous form induces development of CD4-CD8-B220+ T cells and lymphadenopathy in MRL and C57BL/6 mice. Although the propensity for excessive production of T cells is related to an intrinsic T cell defect, a thymus is also required because neonatal thymectomy eliminates lymphadenopathy. Recent evidence suggests that excessive production and release of autoreactive T cells from the thymus of lpr/lpr mice might lead to downregulation of CD4 and CD8 as a "fail safe" tolerance mechanism that occurs during late thymic or post-thymic development. To test this hypothesis, T cell receptor (TCR) transgenic mice that produce large numbers of immature thymocytes recognizing the H-2Db and male H-Y antigens were backcrossed with C57BL/6-lpr/lpr mice and MRL-lpr/lpr mice. It was predicted that Db male lpr/lpr mice would produce large numbers of autoreactive T cells during early thymic development that would lead to an accelerated lymphoproliferative disease. In contrast, Db female lpr/lpr mice would produce large numbers of Db H-Y-reactive T cells, but might not develop lymphadenopathy because the male H-Y antigen would not be present. Unexpectedly, there was complete elimination of lymphadenopathy in both male and female TCR transgenic lpr/lpr mice. The elimination of lymphadenopathy was not due to a failure of thymic maturation since the thymus of H-2Db female lpr/lpr mice contained nearly normal numbers of mature thymocytes. Elimination of lymphadenopathy was also not due to a lack of autoreactive T cells in the peripheral lymph nodes (LN) since there was an increased syngeneic mixed lymphocyte proliferative response of LNT cells from transgenic lpr/lpr compared with +/+ mice in vitro. Hypergammaglobulinemia and autoantibody production in the transgenic lpr/lpr was present at levels comparable with or higher than control nontransgenic lpr/lpr mice, suggesting a dissociation of autoantibody production from the lymphoproliferative disease in the TCR transgenic mice. Conversely, the development of lymphadenopathy and production of CD4-CD8-B220+ T cells appear to be intimately linked, as both were completely eliminated in T cells expressing the transgenic TCR. We propose that lymphoproliferation and production of CD4-CD8-6B2+ T cells in lpr/lpr mice is related to decreased expression of the TCR, and providing the T cells with a rearranged TCR transgene overcomes this defect.
Mountz
J D
JD
University of Alabama, Department of Medicine, Birmingham 35294.
Zhou
T
T
Eldridge
J
J
Berry
K
K
Blüthmann
H
H
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D015139:Blotting, Southern; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D015342:DNA Probes; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte; D017493:Leukocyte Common Antigens; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D015704:CD4 Antigens; D016827:CD8 Antigens; D015342:DNA Probes; D004247:DNA; D017493:Leukocyte Common Antigens