The Journal of Experimental Medicine
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Published online 26 January 2004 doi:10.1084/jem.20031137
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 3, 323-335
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Massive Thymic Deletion Results in Systemic Autoimmunity through Elimination of CD4+ CD25+ T Regulatory Cells

Fei F. Shih, Laura Mandik-Nayak, Brian T. Wipke, and Paul M. Allen

Department of Pathology and Immunology Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Paul M. Allen, Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: (314) 362-8758; Fax: (314) 362-8888; email: allen{at}wustl.edu

Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti–hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

Key Words: autoimmunity • thymic deletion • arthritis • T regulatory cells • TCR transgenic

The online version of this article contains supplemental material.

B.T. Wipke's present address is Elan Pharmaceuticals, Inc., 800 Gateway Boulevard, Building 800, Room 154B, South San Francisco, CA 94080.

Abbreviations used in this paper: ANA, antinuclear antibodies; d3Ntx, day 3 neonatally thymectomized; GI, gastrointestinal; GPI, glucose-6-phosphate-isomerase; HEL, hen egg lysozyme; mHEL, membrane form of HEL; NOD, nonobese diabetic; SP, single positive; Tg, transgenic; Treg, regulatory T cell.


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