Controlling autoreactivity of CD4 T cells by local tolerance induction.

Abstract

Autoimmune diseases are often caused by the inappropriate activation of CD4 T cells specific for peripheral self-antigens. Since these cells recognize their target antigens in the context of MHC class II molecules on the surface of specialized antigenpresenting cells (APC), the induction of immunity, or alternatively tolerance, of CD4 T cells depends on the release of antigens from peripheral tissues and uptake by APC. To study this process, transgenic mouse models have been established in which experimental self-antigens are expressed under the control of tissue-specific promoters. With the availability of T-cell-receptor (TCR)-transgenic mice specific for the respective antigen, the T-cell response toward such neo self-antigens can be followed directly during the development of the immune system (for review, see Himmerling et al., 1993; Kruisbeek and Amsen, 1996; Mondino et al., 1996) The transgenic mouse model described here has been originally established by D. Hanahan with the intention to study tissue-specific tumorigenesis following expression of a viral oncogene, the SV40 T antigen (Tag), under control of the rat insulin II gene promoter (RIP) (Hanahan, 1985). Independent lines of RIP-Tag transgenic mice were later shown to mount characteristic immune responses toward Tag, depending on the onset and level of Tag expression during ontogeny (Adams et al., 1987). Thus, RIP1Tag2 (abbreviated RT2) mice with embryonic onset of Tag expression were found to establish systemic tolerance toward Tag, whereas other lines of mice with delayed onset of Tag expression developed a spontaneous autoimmune response against their pancreatic/3 cells (Skowronski et al., 1990; Jolicoeur et al., 1994; F6rster et al., 1995). With the aim of generating Tag-specific TCRtransgenic mice to study the mechanism of induction of tolerance versus autoimmunity in this system, we identified and cloned a MHC class II restricted Tagspecific TCR that was expressed on Tag-specific CD4 T cells isolated from pancreatic infiltrates of an autoimmune RIP1-Tag5 mouse (F6rster et al., 1995).