Dual T Cell Receptor C~ Chain T Cells in Autoimmunity Materials and Methods

Allelic exclusion at the T cell receptor et locus TCR-ot is incomplete, as demonstrated by the presence of a number of T lymphocyte clones carrying two expressed ot chain products. Such dual 0t chain T cells have been proposed to play a role in autoimmunity, for example, because of a second TCR-~x[3 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-cx locus, therefore unable to produce dual cx chain T cells. Normal mice have a low but significant proportion o f T cells expressing two cell-surface TCR-ot chains that could be enumerated by comparison to TCR-ot hemizygotes, which have none. Susceptibility to various autoimmune diseases was analyzed in TCR-ot hemizygotes that had 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-ot cells. In contrast, nonobese diabetic (NOD) TCRot hemizygotes are significantly protected from cyclophosphamide-accelerated insulitis and diabetes. Thus, dual ot T cells may play an important role in some but not all autoimmune diseases. Furthermore, since protected and susceptible N O D mice both show strong spontaneous responses to glutamic acid decarboxylase, responses to this antigen, if necessary for diabetetogenesis, are not sufficient.