CD137 signaling interferes with activation and function of CD4+CD25+ regulatory T cells in induced tolerance to experimental autoimmune thyroiditis

Experimental autoimmune thyroiditis (EAT), a model for Hashimoto's thyroiditis, is a T cell-mediated disease inducible with mouse thyroglobulin (mTg). Pretreatment with mTg, however, can induce CD4(+) T cell-mediated tolerance to EAT. We demonstrate that CD4(+)CD25(+) regulatory cells are critical for the tolerance induction, as in vivo depletion of CD25(+) cells abrogated established tolerance, and CD4(+)CD25(+) cells from tolerized mice suppressed mTg-responsive cells in vitro. Importantly, administration of an agonistic CD137 monoclonal antibody (mAb) inhibited tolerance development, and the mediation of established tolerance. CD137 mAb also inhibited the suppression of mTg-responsive cells by CD4(+)CD25(+) cells in vitro. Signaling through CD137 likely resulted in enhancement of the responding inflammatory T cells, as anti-CD137 did not enable CD4(+)CD25(+) T cells to proliferate in response to mTg in vitro. (C) 2003 Elsevier Inc. All rights reserved.