[Frontiers in Bioscience 11, 1234-1243, May 1, 2006]

Tolerance to autoimmune thyroiditis: CD4+CD25+ regulatory T cells influence susceptibility but do not supersede MHC class II restriction

Gerald P. Morris and Yi-chi M. Kong

Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Influence of CD4+CD25+ Regulatory T Cells on Susceptibility to Experimental Autoimmune Thyroiditis (EAT)
3.1. Antigen-Specific Induction of EAT Tolerance
3.2. Characteristics of CD4+CD25+ Regulatory T Cells in EAT Tolerance
3.3. Naturally-Existing CD4+CD25+ Regulatory T Cells in Self Tolerance
3.4. Cytokines in the Function of CD4+CD25+ Regulatory T Cells
4. Influence of Major Histocompatibility Complex (MHC) Class II Genes on EAT Susceptibility
5. CD4+CD25+ T Cell Regulation Does Not Supersede the Requirement for Correct MHC Class II Presentation in EAT Susceptibility
6. Perspective
7. Acknowledgment
8. References

1. ABSTRACT

Murine experimental autoimmune thyroiditis (EAT), a model of Hashimoto's thyroiditis, has served for more than three decades as a prototypical model of T cell-mediated autoimmunity. Early investigations demonstrated a clear correlation between genetic factors, particularly the H2A locus of the MHC class II region, and susceptibility to autoimmune thyroiditis. Early studies also demonstrated that susceptibility to EAT induction could be modulated by manipulation of circulating levels of thyroglobulin (Tg), the principal thyroid antigen, resulting in the strengthening of self-tolerance. This antigen-specific induced tolerance is mediated by thymus-derived cells, and subsequent investigations revealed that the suppressive function is located in the CD4+CD25+ T cell subset, similar to findings in other models. We have demonstrated that these CD4+CD25+ regulatory T cells (Treg) influence susceptibility to thyroiditis in naive, as well as mTg-tolerized mice. Here, we describe the influence of both Treg and MHC class II haplotype, independently, as well in combination, and describe our recent utilization of MHC class II transgenic mice to directly compare the extent of their influences.