T-cell receptor-derived peptides in immunoregulation and therapy of retrovirally induced immunosuppression

Retrovirally infected humans and mice showed progressive acquired immunodef iciency 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 o f human V beta8, and that both species showed reactivity to the same sequen ce. Either prophylactic or therapeutic administration of this peptide to re trovirus-infected C57/BL/6 mice normalized the balance of T(H)1- and T(H)2- type helper activity and restored the resistance to infection by the opport unistic parasite Cryptosporidium. Administration of the peptide did not gen erate significantly increased levels of autoantibody, but had a profound ef fect on T-cell activity as well as other aspects of inflammation, including NK-cell activity. A 16-mer derived from the J beta sequence showed similar functional effects on T cells from retrovirus-infected mice. Direct bindin g of the V beta CDR1 peptide to recombinant TCR V alpha /V beta constructs, as well as to IgM natural autoantibodies, suggests that the cell surface r eceptor for the peptide is the alpha/beta TCR on T cells and surface IgM in B cells. The V beta CDR1 peptide stimulated division of murine splenocytes in vitro, stimulated the production of the T(H)1 cytokine IL-2, and synerg ized with the T-cell mitogen concanavalin A in proliferation and IL-2 produ ction. 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 over all T-cell functional capacity, particularly with respect to the cytokine p roduction characteristic of T(H)1-type cells. Our studies are interpreted i n the context of other recent investigations of immunomodulatory peptides.