B7-H4, a newly identified B7 family molecule, is reported to regulate T cell activation. However, the expression and function of B7-H4 remain controversial. Here, we demonstrated that B7-H4 expression in immune cells was undetectable at both the transcription and cell-surface protein levels. B7-H4 transfectants augmented anti-CD3 mAb-induced re-directed cytotoxicity and this was inhibited by anti-B7-H4 mAb. In a hapten-induced contact hypersensitivity model, treatment with anti-B7-H4 mAb at sensitization, but not at challenge, efficiently suppressed the ear swelling and CD8(+) T cell activation assessed by CD25 expression and IFN-gamma production. We found that cells expressing B7-H4 secreted soluble B7-H4 and the serum B7-H4 level increased with disease progression in lupus-prone and collagen-induced arthritis autoimmune mice and after the antigen challenge in allergic inflammatory diseases. Our results suggest a different action of B7-H4 in T cell-mediated inflammatory responses and the possible involvement of soluble B7-H4 in inflammatory immune responses. (C) 2009 Elsevier Inc. All rights reserved.