Autoimmune thyroiditis: A model uniquely suited to probe regulatory T cell function

Abstract

Murine experimental autoimmune thyroiditis (EAT) is a model for Hashimoto’s thyroiditis that has served as a prototype of T cell-mediated autoimmunity for more than three decades. Key roles for MHC restriction and autoantigen influence on susceptibility to autoimmunity have been demonstrated in EAT. Moreover, it has served a unique role in investigations of self tolerance. In the early 1980s, self tolerance and resistance to EAT induction could be enhanced by increasing circulating levels of the autoantigen, thyroglobulin (Tg), by exogenous addition as well as endogenous release. This observation, directly linking circulating self antigen to self tolerance, led to subsequent investigations of the role of regulatory T cells (Tregs) in self tolerance. These studies revealed that protection against autoimmunity, in both naive and tolerized mice, was mediated by thymically-derived CD4+CD25+Foxp3+ Tregs. Moreover, these naturally-existing Tregs required proper costimulation, in context with autoantigen presentation, to maintain and enhance self tolerance. In particular was the selected use of MHC- and heterologous Tg-restricted models from both conventional and transgenic mice. These models helped to elucidate the complex interplay between autoantigen presentation and MHC class II-mediated T cell selection in the development of Treg and autoreactive T cell repertoires determining susceptibility to autoimmunity. Here we describe these investigations in further detail, providing a context for how EAT has helped shape our understanding of self tolerance and autoimmunity.

Enhanced Autoimmunity Associated with Induction of Tumor Immunity in Thyroiditis-Susceptible Mice

“…Also, where prior EAT development had occurred as with 10,000-20,000 U IL-1, further Treg depletion and soluble mTg treatment as could be expected from physiologic release of mTg into the circulation had no discernible effect. This observation is in line with normal Treg function, where it is most efficient in preventing the activation of autoreactive T cells, rather than inhibiting an ongoing autoimmune response (12,25). Moreover, we have shown that Tregs influence susceptibility but do not supersede MHC class II restriction (26).…”

Selenium upregulates CD4<SUP>+</SUP>CD25<SUP>+</SUP> regulatory T cells in iodine-induced autoimmune thyroiditis model of NOD.H-2<SUP>h4</SUP> mice

“…Adoptive transfer of CD4 + CD25 + T cells restored resistance to experimental autoimmune thyroidits (EAT) induction in CD25 + T cell-depleted B10 mice [19]. Recent studies also show that Treg depletion enables thyroiditis induction with mouse thyroglobulin (mTg) in traditionally-resistant mice and mTg-induced, Treg-mediated tolerance protects against EAT induction in genetically-susceptible mice [20]. The naturally-existing CD4 + CD25 + Foxp3 + Tregs influence the thyroiditis development in naive susceptible mice and are required for induction of antigen-specific tolerance [21].…”

Dynamic Changes of CD4+CD25+ Regulatory T Cells in NOD.H-2h4 Mice with Iodine-Induced Autoimmune Thyroiditis

“…Foxp3 transduction in naive T cells also upregulates the expression of CD25 and other Treg-associated cell-surface molecules, such as cytotoxic Tcell-associated antigen-4 (CTLA-4) and glucocorticoid-induced TNF receptor familyrelated gene/protein (GITR) [16]. Treg depletion enables thyroiditis induction with MTg in traditionally resistant mice and MTg-induced, Treg-mediated tolerance protects against experimental autoimmune thyroidits (EAT) induction in genetically susceptible mice [17]. Adoptive transfer of CD4 + CD25 + T cells restored resistance to EAT induction in CD25 + Tcell-depleted B10 mice [18].…”