Evidence that clonal anergy is induced in thymic migrant cells after anti-CD4-mediated transplantation tolerance.
Diabetic (B6) (IE-) mice treated with a depleting regimen of anti-CD4 monoclonal antibody at the time of transplantation with A/J (IEK) islets of Langerhans showed indefinite acceptance of their islet allograft, as evidenced by persistent normoglycemia. To address the mechanisms involved in such anti-CD4 induced transplantation tolerance we studied potentially IE-reactive V beta 11+ T cells from the tolerant allografted mice. Following complete repopulation of the CD4+ cells, both the CD4+V beta 11+ and CD8+V beta 11+ T cell subsets of the transplanted mice were unresponsive to anti-V beta 11 specific crosslinking. In contrast, lymphocytes tested within the first ten days following transplant were responsive to anti-V beta 11 specific crosslinking; this response decreased as a function of time and reached background levels by day 120 posttransplant. Sorting experiments indicated that the response of lymphocytes to anti-V beta 11 specific crosslinking seen during the initial 120 days posttransplant was confined to the peripheral CD8+ cells; the repopulating CD4+V beta 11+ T cells were unresponsive. In addition, administration of r-IL-2 at the time of transplantation induced rejection in anti-CD4-treated animals, again indicating that the peripheral CD8+ cells could respond shortly after transplant if provided with appropriate help. The decreasing response of CD8+ T cells from transplanted animals to anti-V beta 11 stimulation was inversely correlated with the rate of migration of cells from the thymus to the periphery, implying that new thymic migrant V beta 11+ cells, both CD4+ and CD8+, were rendered anergic upon encountering peripheral alloantigen. These data suggest the possibility that recent thymic migrants are rendered anergic upon encountering antigen in the periphery, a simple model to serve as a "fail-safe" mechanism to prevent autoreactivity.
Alters
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Department of Medicine, Stanford University School of Medicine, California 94305-5111.
Song
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HK
Fathman
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CG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000032:analysis; D002465:Cell Movement; D002469:Cell Separation; D017635:Clonal Anergy / Q000276:immunology; D006084:Graft Rejection / Q000139:chemically induced / Q000209:etiology; D007376:Interleukin-2 / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007700:Kinetics; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D007376:Interleukin-2; D011994:Recombinant Proteins