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 Vbeta8, and that both species showed reactivity to the same sequence. Either prophylactic or therapeutic administration of this peptide to retrovirus-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 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 Jbeta sequence showed similar functional effects on T cells from retrovirus-infected mice. Direct binding of the VbetaCDR1 peptide to recombinant TCR Valpha/Vbeta constructs, as well as to IgM natural autoantibodies, suggests that the cell surface receptor for the peptide is the alpha/beta TCR on T cells and surface IgM in B cells. The Vbeta CDR1 peptide stimulated division of murine splenocytes in vitro, stimulated the production of the T(H)1 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 T(H)1-type cells. Our studies are interpreted in the context of other recent investigations of immunomodulatory peptides.