Murine experimental autoimmune thyroiditis (EAT) has served as a model in studies of autoimmune diseases for nearly 3 decades, due to the early recognition of the association of major histocompatibility complex (MHC) with susceptibility, and the identification of thyroglobulin (Tg) as an autoantigen. In 1981, we demonstrated the presence of autoreactive T cells responding to syngeneic mouse (m) Tg immunization in a susceptible strain (ElRehewy et al., 1981) and in 1982, we pinpointed EAT susceptibility to H2A class II genes (Beisel et al., 1982). Also, in 1982, we reported the induction of resistance with mTg, either from exogenous source or from endogenous release by thyroid-stimulating hormone (TSH) (Kong et al., 1982). This resistance was specific and protected mice from EAT induction. The cells with suppressive function were thymus-derived. We hypothesized that, in normal susceptible individuals, there is a clonal balance of suppressor T cells, keeping the autoreactive T cells in check. This balance toward suppression or autoimmunity can shift according to tolerogenic and immunogenic signals. Subsequent availability of CD4 and CD8 monoclonal antibodies (mAbs) enabled the allocation of suppressor T cells to the CD4subset in 1989 (Kong et al., 1989). The recent availability of CD25-depleting mAb further characterized them as CD4?CD25(Morris et al., 2003). Clearly, the early mTg-specific suppressor T cell is one and the same as the current CD4?CD25regulatory T cell. This chapter briefly reviews the progressive characterization of CD4?CD25regulatory T cells in EAT. The known class II association has enabled a comparison of their contribution to susceptibility and resistance. We have also examined their role in a recently uncovered H2E(H2A?) transgenic mouse model, which responds to EAT induction with human (h) Tg, but not mTg. Depletion of CD4?CD25regulatory T cells did not alter this stringent H2E restriction. Thus, while CD4?CD25T cell regulation can modulate EAT development, it does not supersede MHC restriction for certain Tg epitopes.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)