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ISSN: 1040-8401 Print
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Pages: 310
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T-Cell Receptor-Derived Peptides in Immunoregulation and Therapy of Retrovirally Induced Immunosuppression
John J. Marchalonis
Department of Immunobiology, University of Arizona College of Medicine P.O. Box 24-5049 Tucson, AZ 85724
Ian F. Robey
Arizona Cancer Center; Microbiology and Immunology, College of Medicine, University of Arizona, Tucson, AZ 85724
Allen B. Edmundson
Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
R. Tomas Sepulveda
Microbiology and Immunology, College of Medicine, and College of Public Health, University of Arizona, Tucson, AZ 85724
Ronald R. Watson
2College of Public Health, University of Arizona, Tucson, AZ 85724
ABSTRACT
Retrovirally infected humans and mice showed progressive acquired immunodeficiency accompanied by the production of elevated levels of autoantibodies directed against T-cell receptor variable-domain epitopes. Epitope mapping analyses indicated that a major determinant recognized was defined by a 16-mer peptide containing the entire CDR1 segment and part of the FR2 region of human Vb8, and that both species showed reactivity to the same sequence. Either prophylactic or therapeutic administration of this peptide to retrovirusinfected C57/BL/6 mice normalized the balance of TH1- and TH2-type helper activity and restored the resistance to infection by the opportunistic parasite Cryptosporidium. Administration of the peptide did not generate significantly increased levels of autoantibody, but had a profound effect on T-cell activity as well as other aspects of inflammation, including NK-cell activity. A 16-mer derived from the Jb sequence showed similar functional effects on T cells from retrovirus-infected mice. Direct binding of the Vb CDR1 peptide to recombinant TCR Va/Vb constructs, as well as to IgM natural autoantibodies, suggests that the cell surface receptor for the peptide is the a/b TCR on T cells and surface IgM in B cells. The Vb CDR1 peptide stimulated division of murine splenocytes in vitro, stimulated the production of the TH1 cytokine IL-2, and synergized with the T-cell mitogen concanavalin A in proliferation and IL-2 production. These studies indicate that administration of peptides derived from T-cell receptor variable domains to animals immunosuppressed as a result of retroviral infection has a profound immunomodulatory effect enhancing overall T-cell functional capacity, particularly with respect to the cytokine production characteristic of TH1-type cells. Our studies are interpreted in the context of other recent investigations of immunomodulatory peptides.
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