Dual-receptor T cells expressing one self-restricted TCR.

Abstract

During thymic development, T cells rearrange and express genes encoding clonotypic T-cell receptors (TCR), and undergo selective events involving interactions between TCR and thymic major histocompatibility complex (MHC) molecules. Recent studies indicate that up to 30% of peripheral T cells may express two TCR, that both TCR on these cells are functional, and that dual-specific T cells can promote autoimmunity. Here we demonstrate that dual-receptor T cells are readily generated in class II-deficient (class II-) mice expressing the class II-restricted AND TCR transgene (TCRtg). While this TCRtg is unable to promote positive selection in class II- mice, T cells arise in class II-TCR+tg mice by co-expressing non-transgenic endogenous TCR that permit positive selection on class I molecules. Our findings indicate that when a rearranged TCR fails to promote positive selection on self MHC molecules, expression of a second receptor can rescue the developing T cell. Accordingly, many dual-receptor T cells may actually be mono-specific in vivo, possessing only one self MHC-restricted TCR, and therefore should not require unique regulatory controls to prevent autoreactivity.