Persistent suppression of virus-specific cytotoxic T cell responses after transient depletion of CD4+ T cells in vivo.
Co-administration of soluble Ag and anti-CD4 mAb has been successfully used to induce long term Ag-specific tolerance. The mechanisms underlying persistent immunologic unresponsiveness are unclear. We have now studied whether tolerance toward complex viral Ag expressed on Moloney sarcoma virus (MSV)-transformed tumor cells can be induced when given at the time of severe helper cell depletion. Although mice that had been injected with anti-CD4 mAb at the time of immunization regained the ability to recognize MSV Ag, their humoral and cytotoxic immunity to MSV were severely compromised. Ag-specific low responsiveness was maintained for more than 6 mo. To analyze the T cell repertoire of low responder mice we have estimated precursor frequencies of MSV-specific proliferative and cytotoxic T cells after the CD4+ T cell subset was fully reconstituted. There was no difference in the frequencies of control and low responder mice excluding clonal deletion as the mechanism maintaining low responsiveness. In co-culture experiments the defect in low responder mice could be localized to the regenerated CD4+ T cell subset, suggesting the induction of CD4+ suppressor-inducer cells. Alternatively, regenerated CD4+ cells in anti-CD4 conditioned mice had acquired a defect to provide help for MSV-specific responses. In spite of the potentials to induce low responsiveness to selected Ag by anti-CD4 conditioning, the risk to cause persistent virus-specific immunodeficiency might limit the clinical application of anti-CD4 therapy.
Goronzy
J J
JJ
Department of Medicine, University of Heidelberg, West Germany.
Weyand
C M
CM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000494:pharmacology; D007958:Leukocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008980:Moloney murine sarcoma virus / Q000276:immunology; D013234:Stem Cells; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000382:microbiology; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D007376:Interleukin-2