Dual T cell receptor α chain T cells in autoimmunity

Abstract

Allelic exclusion at the T cell receptor α locus TCR-α is incomplete, as demonstrated by the presence of a number of T lymphocyte clones carrying two expressed α chain products. Such dual α chain T cells have been proposed to play a role in autoimmunity, for example, because of a second TCR-αβ pair having bypassed negative selection by virtue of low expression. We examined this hypothesis by generating mice of various autoimmunity-prone strains carrying a hemizygous targeted disruption of the TCR-α locus, therefore unable to produce dual α chain T cells. Normal mice have a low but significant proportion of T cells expressing two cell-surface TCR-α chains that could be enumerated by comparison to TCR-α hemizygotes, which have none. Susceptibility to various autoimmune diseases was analyzed in TCR-α hemizygotes that bad been backcrossed to disease-prone strains for several generations. The incidence of experimental allergic encephalomyelitis and of lupus is not affected by the absence of dual TCR-α cells. In contrast, nonobese diabetic (NOD) TCRα hemizygotes are significantly protected from cyclophosphamide-accelerated insulitis and diabetes. Thus, dual α T cells may play an important role in some but not all autoimmune diseases. Furthermore, since protected and susceptible NOD mice both show strong spontaneous responses to glutamic acid decarboxylase, responses to this antigen, if necessary for diabetetogenesis, are not sufficient.