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Homeostatic Proliferation in the Mice with Germline FoxP3 Mutation and its Contribution to Fatal Autoimmunity¹

Xing Chang^*, Pan Zheng^*, and Yang Liu^2,*,

^* Division of Immunotherapy, Section of General Surgery, Department of Surgery, Department of Pathology, and Division of Molecular Medicine and Genetics, Department of Internal Medicine and Pathology, Comprehensive Cancer Center and Program of Molecular Mechanisms of Disease, University of Michigan Medical Center, Ann Arbor, MI 48109

FoxP3 has emerged as a critical regulator for the development and function of regulatory T cells. Recent studies by several groups have demonstrated that FoxP3 is expressed outside T cell lineages. In this context, we have reported that germline mutation of FoxP3 caused defective thymopoiesis, although its potential contribution to autoimmune diseases has not been analyzed. In this study, we report that, during perinatal period, germline mutation of FoxP3 in scurfy mice caused lymphopenia in the spleen and massive homeostatic proliferation, characterized by the independence from cognate Ags and expression of bona fide markers for homeostatic proliferation. The homeostatic proliferation is suppressed by increases in T cell numbers but not by adoptive transfer of regulatory T cells (Treg). Adoptive transfer of Treg-containing bulk T cells was dramatically more effective than transfer of either Treg alone or Treg-depleted CD4 T cells in curing the scurfy mice. Our data demonstrated that FoxP3 mutation not only ablates Treg, but also dramatically increased homeostatic proliferation during the perinatal period. Homeostatic proliferation acts in concert with Treg defects in causing acute and fatal autoimmune diseases in the FoxP3 mutant mice. These results demonstrated that germline mutation of FoxP3 caused two defects that work in concert to cause lethal autoimmunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the U.S. Department of Defense and National Institutes of Health.

² Address correspondence and reprint requests to Dr. Yang Liu, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109. E-mail address: yangl{at}umich.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; WT, wild type; IPEX, immune dysregulation, polyendocrinopathy, X-linked syndrome.