T cell stimulation in the absence of a second, costimulatory signal can lead to anergy or the induction of cell death. CD28 is a major T cell costimulatory receptor, the coengagement of which can prevent anergy and cell death. The CD28 receptor is a member of a complex family of polypeptides that includes at least two receptors and two ligands. Cytotoxic lymphocyte-associated molecule-4 (CTLA-4, CD152) is the second member of the CD28 receptor family. The ligands or counterreceptors for these two proteins are the B7 family members, CD80 (B7-1) and CD86 (B7-2). This article reviews the CD28/CTLA4 and CD80/CD86 families, and outlines the functional outcomes and biochemical signaling pathways recruited after CD28 ligation.

In RBL-2H3 rat tumor mast cells, cross- The RBL-2H3 rat tumor mast cell line has proven to be an excellent experimental model for studies of receptormediated cell activation. Antigen-mediated cross-linking of the high-affinity IgE receptor, FceRI, on these cells leads to Ca2+ influx, phosphatidylinositol turnover, release of serotonin and other substances from granules, polymerization of actin, and transformation of the cell surface from a microvillous to a lamellar architecture (reviewed in refs. 1 and 2). These antigen-stimulated responses are inhibited by tyrosine kinase inhibitors and enhanced by tyrosine phosphatase inhibitors, suggesting the involvement of a receptorstimulated protein-tyrosine kinase(s) in FcERI-mediated RBL-2H3 cell activation (3, 4). The discovery that antigen binding stimulates tyrosine phosphorylation of multiple RBL-2H3 cell proteins supported this hypothesis (5-8 9107The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Ligation of either CD80 (B7-1) or CD86 (B7-2), two principal ligands for CD28, is thought to skew the immune response toward Th1 or Th2 differentiation. We have examined early signal transduction pathways recruited following T cell stimulation with either CD80 or CD86. Purified human peripheral T cells or Jurkat T cells were stimulated with Chinese hamster ovary (CHO) cells expressing either human CD80 (CHO-CD80) or human CD86 (CHO-CD86) or with anti-CD28 monoclonal antibody (mAb). In the presence of phorbol 12-myristate 13-acetate, both CHO-CD80 and CHO-CD86, like anti-CD28 mAb, were capable of stimulating cytokine production from both human peripheral T cells and Jurkat T cells. Both CHO-CD80 and CHO-CD86, in the presence of anti-CD3 mAb, costimulated NFAT-dependent transcriptional activation. Several intracellular signaling proteins, such as CBL and VAV, were phosphorylated on tyrosine in response to CD80, CD86, and anti-CD28 mAb. Surprisingly, although stimulation of Jurkat T cells with either CHO-CD80 or anti-CD28 mAb resulted in robust tyrosine phosphorylation of CD28 itself, ligation with CHO-CD86 was unable to induce detectable CD28 tyrosyl phosphorylation over a range of stimulation conditions. In addition, the association of phosphoinositide 3-kinase with CD28 and enhanced tyrosine phosphorylation of phospholipase C␥ were seen after anti-CD28 mAb and CHO-CD80 stimulation but to a much lesser extent after CHO-CD86 stimulation. Thus, ligation of CD28 with either CD80 or CD86 leads to shared early signal transduction events such as the tyrosine phosphorylation of CBL and VAV, to NFAT-mediated transcriptional activation, and to the costimulation of interleukin-2 and granulocyte-macrophage colonystimulating factor production. However, CD80 and CD86 also induce distinct signal transduction pathways including the tyrosine phosphorylation of CD28 and phospholipase C␥1 and the SH2-dependent association of phosphoinositide 3-kinase with CD28. These quantitative, if not qualitative, differences between signaling initiated by these two ligands for CD28 may contribute to functional differences (e.g. Th1 or Th2 differentiation) in T cell responses.Activation and maturation of resting T lymphocytes can be achieved by antigen-specific interactions of the TcR-CD3 complex in concert with a second, antigen-nonspecific signal. This second, costimulatory signal has been shown to prevent the induction of T cell anergy and to enhance cytokine production, notably IL-2 1 (1-3). Found on more than 95% of human CD4 ϩ T cells and on about 50% of human CD8 ϩ T cells, the cellsurface molecule CD28 is a major T cell costimulatory receptor. Engagement of the CD28 receptor with anti-CD28 mAb or by ligand prevents the induction of T cell anergy and supports IL-2 production and T cell proliferation.The B7 family members CD80 (B7-1) and CD86 (B7-2) are two principal ligands for CD28 and for CTLA-4 (CD152), a second CD28 family member. Whereas only 25% homologous by amino acid sequence, CD80 and CD86 bind CD28 with similar low affinities ...