T Cell Receptor Signalling Defects in Anergic T Cell Induced in vivo by Bacterial Superantigen

Abstract

Although mice inherit a large number of gene segments of T cell receptor (TCR) α- and β- chain variable domains (Vα, Vβ), generally not every V gene takes part in the repertoire of T cells in the periphery. This development of a limited TCR repertoire results from thymic negative selection where apoptic cell death plays a major role in the loss of self-reactive immature T cells (Kappler 1987). This type of thymus dependent “self-tolerance” is under the striking influence of self-genome integrated mouse mammary tumour virus encoded superantigens (previously denoted as minor lymphocyte stimulating antigens) that react with T cells based on the particular Vβ phenotypes (Kappler 1988; MacDonald 1988). In contrast, peripheral T cell tolerance against foreign antigens is caused, at least in part, by functional unresponsiveness (anergy). Mice tolerized to allogenic viral superantigens or bacterial superantigens give rise to anergized T cells expressing specific TCR Vβ’s (Rammensee 1989; Kawabe and Ochi 1990). Anergic T cells are also implicated in transgenic mice expressing nonself antigens in the periphery (Burkly 1989; Murphy 1989: Wieties 1990), or self reactive TCRs (Blackman 1991), and mice tolerized orally to nonself protein antigens (Whitacre 1991). Anergic T cells fail to proliferate or produce the T cell growth factor, interleukin-2 (IL-2) in response to antigenic stimulation. Though the fate of these functionally inactive cells is not yet clear, circumstantial evidence suggests that most but perhaps not all of the anergic T cells recover from anergy (Migita & Ochi submitted). A fundamental role of anergic T cells in T cell memory has also been suggested (Bandeira 1991). Assuming that anergy represents an antigen induced transient state of mature T cells in the periphery, and that anergic T cells represent a novel, functional T cell subset, it appears to be important to elucidate the mechanism of T cell anergy.