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 Blood, 15 August 2007, Vol. 110, No. 4, pp. 1199-1206.
Prepublished online as a Blood First Edition Paper on April 26, 2007; DOI 10.1182/blood-2006-10-054585.

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IMMUNOBIOLOGY

Role of CD28 in fatal autoimmune disorder in scurfy mice

Nagendra Singh1, Phillip R. Chandler1, Yoichi Seki1, Babak Baban1, Mayuko Takezaki1, David J. Kahler1, David H. Munn1, Christian P. Larsen2, Andrew L. Mellor1, and Makio Iwashima1

1 Immunotherapy Center, Medical College of Georgia, Augusta; and 2 Emory Transplant Center, Department of Surgery, and Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Georgia

Scurfy mice develop CD4 T-cell–mediated lymphoproliferative disease leading to death within 4 weeks of age. The scurfy mutation causes loss of function of the foxp3 gene (foxp3sf), which is essential for development and maintenance of naturally occurring regulatory CD4 T cells (nTregs). In humans, mutations of the foxp3 gene cause immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX). In most patients with IPEX and also in scurfy mice, T cells show hyperreactivity and levels of Th1- and Th2-associated cytokines are substantially elevated. We report that removal of CD28 expression rescued scurfy mice from early death. Longer-term surviving CD28-deficient scurfy mice still had lymphoproliferative disorder, but their CD4 T cells showed decreased interferon-{gamma} and no sign of interleukin-4 or interleukin-10 hyperproduction. Furthermore, injection of CTLA4-Ig to block CD28-B7 interactions substantially improved the survival of scurfy mice by blocking effector T-cell differentiation. These data support the hypothesis that CD28-B7 interactions play a critical role in the etiology of lethal autoimmune disease in scurfy mice by stimulating the differentiation of antigen-activated naive T cells into effector T cells.


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