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Generation and Characterization of B7-H4/B7S1/B7x-Deficient Mice

Woong-Kyung Suh,^1,4,5* Seng Wang,² Gordon S. Duncan,¹ Yoshiyuki Miyazaki,² Elizabeth Cates,³ Tina Walker,³ Beata U. Gajewska,³ Elissa Deenick,^1,4,5 Wojciech Dawicki,^4, Hitoshi Okada,^1,5 Andrew Wakeham,¹ Annick Itie,¹ Tania H. Watts,⁴ Pamela S. Ohashi,^1,4,5 Manel Jordana,³ Hiroki Yoshida,² and Tak W. Mak^1,4,5*

Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2C1,¹ Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan,² Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada L8N 3Z5,³ Departments of Immunology,⁴ Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5S 1A8⁵

Received 1 May 2006/ Returned for modification 10 June 2006/ Accepted 24 June 2006

Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.

Present address: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.