IL-12 prevents tolerance induction with mouse thyroglobulin by priming pathogenic T cells in experimental autoimmune thyroiditis: Role of IFN-gamma and the costimulatory molecules CD40L and CD28

Deaggregated mouse thyroglobulin (dMTg) induces tolerance to experimental a utoimmune thyroiditis (EAT), a Th1-cell-mediated disease. To test whether I L-12, a potent activator of Th1 cells, can overcome tolerance induction, di fferent doses of IL-12 were given to CBA/J mice during the critical interva l of 2-3 days after dMTg administration. After challenge with MTg/LPS, dMTg /IL-12-pretreated mice showed more extensive thyroiditis than immunized con trols, but comparable levels of anti-MTg and T cell proliferation. Without challenge, few MTg antibodies were produced. In contrast, pretreatment with dMTg/poly A:U or dMTg/IL-1, two other T cell activators which also interfe re with tolerance induction, induced antibodies before challenge, but not m ore severe thyroiditis. Mice pretreated with IL-12 without dMTg developed t hyroiditis comparable to immunized controls, but less severe thyroiditis th an dMTg/IL-12-pretreated mice. Clearly, IL-12 not only blocked tolerance in duction, but also primed antigen-specific T cells during the tolerogenic pe riod of dMTg pretreatment, resulting in stronger thyroiditis than immunizat ion only. Neither treatment with anti-IFN-gamma nor the use of IFN-gamma kn ockout mice altered the capacity of IL-12 to prevent tolerance induction. H owever, both anti-CD28 and anti-CD40L antibodies diminished the priming eff ect by dMTg/IL-12. The mechanisms of IL-12 action include priming of MTg-sp ecific T cells and the involvement of T cell costimulatory molecules. (C) 2 001 Academic Press.