T cells with two functional antigen-specific receptors

Although the clonal selection theory states that lymphocytes should bear only a single specificity of receptor, there is much evidence that some T cells, at least, bear two receptors. Here, we have used mice transgenic for genes encoding an autoreactive T-cell receptor (TCR) to examine the specificity of T cells bearing two functional TCRs. We find that T cells developing in mice that do not express the major histocompatibility complex (MHC) molecule recognized as self by the transgene-encoded TCR express both this TCR and a second TCR that is specific for the MHC molecules of the strain in which it arose. Thus, these T cells have two TCRs, each specific for a distinct antigen bound to a distinct MHC molecule. In contrast, when raised in mice bearing the MHC for which the receptor is specific, T cells develop that express the transgene-encoded TCR almost exclusively. Such mice are highly susceptible to autoimmune disease. Our data suggest that on most T cells bearing two TCRs, only one is specific for peptides bound to self-MHC molecules and, thus, that expression of two TCRs does not usually confer reactivity to two unrelated antigens.