DUAL T-CELL RECEPTOR ALPHA-CHAIN T-CELLS IN AUTOIMMUNITY

Allelic exclusion at the T cell receptor alpha locus TCR-alpha is inco mplete, as demonstrated by the presence of a number of T lymphocyte cl ones carrying two expressed alpha chain products. Such dual alpha chai n T cells have been proposed to play a role in autoimmunity, for examp le, because of a second TCR-alpha beta pair having bypassed negative s election by virtue of low expression. We examined this hypothesis by g enerating mice of various autoimmunity-prone strains carrying a hemizy gous targeted disruption of the TCR-alpha locus, therefore unable to p roduce dual alpha chain T cells. Normal mice have a low but significan t proportion of T cells expressing two cell-surface TCR-alpha chains t hat could be enumerated by comparison to TCR-alpha hemizygotes, which have none. Susceptibility to various autoimmune diseases was analyzed in TCR-alpha hemizygotes that had been backcrossed to disease-prone st rains for several generations. The incidence of experimental allergic encephalomyelitis and of lupus is not affected by the absence of dual TCR-alpha cells. In contrast, nonobese diabetic (NOD) TCR alpha hemizy gotes are significantly protected from cyclophosphamide-accelerated in sulitis and diabetes. Thus, dual alpha T cells may play an important r ole in some but not all autoimmune diseases. Furthermore, since protec ted and susceptible NOD mice both show strong spontaneous responses to glutamic acid decarboxylase, responses to this antigen, if necessary for diabetetogenesis, are not sufficient.