Human anti-idiotypic T lymphocyte clones are activated by autologous anti-rabies virus antibodies presented in association with HLA-DQ molecules.

Abstract

The regulatory function of antigen-specific T cells in human antibody responses to protein and carbohydrate determinants of many viral and bacterial antigens has extensively been studied in systems involving in vitro triggering of B cells by antigens or polyclonal activators. Although amply documented in experimental murine models, the existence of T helper cells with receptor specificity for idiotypic determinants of B cell immunoglobulins has not been demonstrated in a human system. We are interested in T helper cell recognition of idiotypic determinants of virus-specific antibody, secreted by human B cells in response to viral antigens, and in the role which such idiotype-specific T helper cells play, alone or in concert with virus-specific T helper cells, to regulate the antibody response. Understanding of the function of different T helper cell subsets in an anti-viral antibody response and especially of the mechanisms of idiotype recognition by T cells is important for the development, and future application in man of idiotype vaccines, the potential of which has been indicated for different pathogens in several animal species. It was realized that for the efficient characterization of each of the T helper cell subsets, the availability of cloned populations of T cells would be inevitable. Furthermore, we argued that if, as predicted by Jerne, idiotype recognizing T helper cells are involved in physiological idiotype regulation in the course of an immune response--e.g., following encounter with virus--cloned populations of T cells should best be obtained by immunization protocols closely mimicking the physiological situation. In a previous report we described the induction of a secondary antibody response in human peripheral blood mononuclear cells (PBMC) in vitro by rabies virus antigen. This response was shown to be T helper cell dependent, and rabies virus-specific T helper cell clones have recently been obtained in our laboratory. The present study describes the generation of cloned lines of anti-idiotypic T4+ cells from rabies virus immune PBMC restimulated with rabies virus antigen in vitro. The cloned T cell lines were found to respond to circulating autologous antibody exhibiting specificity to rabies virus, but not to rabies virus antigen. The clonal proliferation, induced by this "auto-anticlonotypic" antibody, was found to be preceded by modulation of the T3/Ti molecular complex and required presentation of the antibodies by antigen presenting cells in association with HLA-DQ molecules. This observation of MHC-restricted idiotype recognition by human T cells, may have important consequences for the understanding of the regulation of th