The contrasting role of B7-H3.

T lymphocytes of adaptive immunity provide vertebrates with the ability to survey for and respond specifically to an incredible diversity of antigens, whether foreign or native. Appropriate T cell response is required to eradicate pathogens, whereas abnormal T cell function could lead to autoimmune diseases, cancer, and transplantation rejection. The outcome of T cell engagement of antigen is determined by positive costimulation and negative coinhibition; both are primarily generated by the interaction between the B7 family and their receptor CD28 family (1). Recent years have seen the identification of several new members of B7/CD28 families. The growing B7 family now comprises seven members: B7-1 (CD80), B7-2 (CD86), B7h (CD275), PD-L1 (CD274), PD-L2 (CD273), B7-H3 (CD276), and B7x (B7-H4 or B7S1). Almost 5 years ago, we divided the B7 family into three groups by phylogenetic analysis: group I includes B7-1, B7-2, and B7h; group II consists of PD-L1 and PD-L2; and group III contains B7x and B7-H3 (2, 3). Receptors for group I are CD28, CTLA-4, and ICOS, and the receptor for group II is PD-1 (Fig. 1). B7-1 also binds PD-L1. One prediction of the phylogenetic comparison was that receptor(s) for B7-H3 would not be real homologue(s) of receptors for group I and II (3). Five years later, this prediction has been proven true (3). In this issue of PNAS, Hasiguchi et al. (3, 4) have identified one such receptor, triggering receptor expressed on myeloid cell (TREM)-like transcript 2 (TLT-2, or TREML2), which binds B7-H3 and costimulates activation of CD8 T cells in particular. TLT-2 is a member of the TREM receptor family (5, 6), which includes TREM-1, -2, and -3, as well as TLT-1 and -2. B7-H3 is the first ligand to be identified for the TREM receptor family. Because the immunological function of B7-H3 has been controversial, the discovery of the B7-H3/TLT-2 pathway is a significant step toward resolving the polarizing data involving the roles of B7-H3 in immune responses as well as the functions of the TREM receptor family. B7-H3 has two forms. Mouse B7-H3 has extracellular IgV-IgC domains, whereas human B7-H3 contains tandemly duplicated IgV-IgC-IgV-IgC domains because of exon duplication (7). No functional difference has been observed between these two forms. B7-H3 is broadly expressed, in contrast to B7-1 and B7-2 whose expression is largely limited to professional antigen-presenting cells (APCs) such as dendritic cells (DCs), macrophages, and B cells. At the transcriptional level, B7-H3 is found in most organs (8, 9). At the protein level, B7-H3 is found in human liver, lung, bladder, testis, prostate, breast, placenta, and lymphoid organs. The exact cell type of B7-H3-positive cells in the organs has yet to be determined. The different expression pattern between mRNA and protein suggests that this molecule has posttranscriptional regulation. However, the molecular mechanisms regulating B7-H3 expression are still unclear. The expression of B7-H3 is induced on T cells, natural killer (NK) cells, and APC (8, 10, 11). B7-H3 is up-regulated during the maturation from monocytes to DC or during the interaction between DC and regulatory T cells. In addition, B7-H3 is found on fibroblasts, fibroblast-like synoviocytes, and epithelial cells. Finally, some human cancers overexpress B7-H3 (1). It has been observed to be overexpressed in prostate cancer, non-small-cell lung cancer, gastric carcinoma, and ovarian cancer. Structurally, B7-H3 is a type I transmembrane protein. However, the majority of this protein is found in the cytoplasm of tumor cells (12, 13). Factors that regulate B7-H3 mRNA translation and protein access to the cell surface can spatially and temporally determine the extent to which tumor-associated B7-H3 regulates T cell function. B7-H3 acts as a T cell costimulator. The work that initially identified human B7-H3 showed that it has a costimulatory effect on T cells (8). In the presence of anti-CD3 antibody, B7-H3 was able to increase proliferation of both the CD4 and CD8 T cell populations and selectively stimulated IFNproduction. In addition, B7-H3 transiently transfected melanoma cells can enhance induction of human primary CD8 cytotoxic T cells (CTLs). Subsequently, in several mouse cancer models it has been shown that ectopic expression of B7-H3 leads to activation of tumor-specific CTLs that are able to slow tumor growth or even completely eradicate tumors (14–16). Mice with a B7-H3transfected colon cell line had significantly prolonged survival times (16). In a P815 mastocytoma model, an immunogenic and B7-H3 negative tumor line, expression of B7-H3 on P815 led to tumor regression in half of the mice (14). P815-associated B7-H3 appears to induce rapid expansion of tumor antigenspecific CTL in vivo. CD4 T cells are not required for the induction of CD8 CTL for tumor immunity because depletion of CD4 T cells did not diminish the resistance of mice to the B7-H3transfected P815 tumor. In a hepatocellular carcinoma model, intratumoral administration of a B7-H3-expressing