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Perinatal Blockade of B7-1 and B7-2 Inhibits Clonal Deletion of Highly Pathogenic Autoreactive T Cells

Jian-Xin Gao, Huiming Zhang, Xue-Feng Bai, Jing Wen, Xincheng Zheng, Jinqing Liu, Pan Zheng and Yang Liu

Department of Pathology and Comprehensive Cancer Center, Division of Cancer Immunology, Ohio State University Medical Center, Columbus, OH 43210

Address correspondence to Yang Liu, Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210. Phone: 614-292-3054; Fax: 614-688-8152; E-mail: liu-3{at}medctr.osu.edu

A number of in vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells. However, the significance of B7-mediated clonal deletion in preventing autoimmune diseases has not been studied systematically. Here we report that the perinatal blockade of B7-1 and B7-2 substantially inhibits the clonal deletion of T cells in the thymus and leads to an accumulation of T cells capable of inducing fatal multiorgan inflammation. These results reveal a critical role for costimulatory molecules B7-1 and B7-2 in deleting pathogenic autoreactive T cells in the thymus. The critical role of B7-1 and B7-2 in T cell clonal deletion may explain, at least in part, the paradoxical increase of autoimmune disease in mice deficient for this family of costimulatory molecules, such as cytotoxic T lymphocyte associated molecule 4, CD28, and B7-2. The strong pathogenicity of the self-reactive T cells supports a central hypothesis in immunology, which is that clonal deletion plays an important role in preventing autoimmune diseases.

Key Words: autoimmunity • clonal deletion • B7-1 and B7-2 • CD28 • CTLA-4

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