T cells expressing two different T cell receptors form a heterogeneous population containing autoreactive clones

Abstract

During T cell development both alleles of the T cell receptor (TCR) alpha locus are rearranged. As a result, a sizeable proportion of T cells can express two distinct TCRs, but the functional significance of this phenomenon remains controversial. Studies on transgenic mice with two TCRs have focused on the risk of immunopathology that such cells may pose, while some have suggested that most dual-specific T cells are nonfunctional or even protective. We tracked the fate and TCR repertoire of single- and dual-specific T cells within a normal polyclonal population undergoing lymphopenia-induced proliferation, a setting which has been shown to cause immunopathology and autoimmunity. After the expansion the repertoire of dual-specific T cells had become highly biased, with both prominent clonal expansions and the complete disappearance of other clones. Our results suggest that the normal repertoire of dual-specific T cells contains both nonfunctional cells and a small, 5% fraction of clones which display a much higher than average affinity to antigens normally tolerated as harmless. This heterogeneity may also help in reconciling some of the earlier, conflicting results.