As we have hypothesized earlier and discussed above, there is a clonal balance of regulatory T cells and autoreactive T cells, with the former keeping the latter in check in normal, susceptible individuals (Kong et al., 1982). This hypothesis has certainly been borne out by transfer experiments in which CD4+CD25- T cells, transferred without CD4+CD25+ T cells, mediated the development of several autoimmune diseases including thyroiditis (Sakaguchi et al., 1995). The depletion of CD4+CD25+ T cells also enabled resistant mice to respond to induction of autoimmune gastritis (McHugh and Shevach, 2002). We have postulated that such a natural barrier to autoimmune thyroiditis development represents the first level of regulatory influence, while mTg-induced resistance to withstand EAT induction represents the second level of regulation (Kong et al., 1989). With the identification of CD4+CD25+ regulatory T cells as mediators of induced resistance, we examined if naturally occurring regulatory T cells were indeed CD4+CD25+ (Morris and Kong, 2004). We used the protocol of inducing EAT with repeated injections of mTg without adjuvant, which generally results in EAT development in about 50% of the animals (ElRehewy et al., 1981). Table 15.1 shows that depletion of CD4+CD25+ T cells before repeated doses of mTg 16 times over 4 weeks greatly increased the incidence of thyroiditis, compared to prior treatment with control IgG. The difference in thyroid infiltration was also accompanied by higher mTg Ab levels and greater in vitro proliferative response to mTg. It thus appears that CD4+CD25+ regulatory T cells naturally exist and maintain peripheral tolerance to self-antigens in EAT.
Table 15.1. In Vivo Depletion of CD4+CD25+ T Cells Lowers the Threshold for EAT
Induction without Adjuvant
Number of mice with % thyroid involvement Incidence
Rat CD25 antibody 2 4 5 9/11 82*
Mice were preinjected i.v. with rat antibody to CD25 or control antibody at days -14 and -10. EAT was induced in susceptible CBA mice by administration of aggregated mouse thyroglobulin (40 |rg) i.v. beginning at day 0, on 4 successive days for 4 weeks. Thyroid pathology was assessed 35 days later. *p < 0.04.
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