Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation?

Howard Hughes Medical Institute Department of Medicine and Department of Molecular Genetics and Cell Biology Gwen Knapp Center for Lupus and Immunology Research University of Chicago Chicago, Illinois 60637 Introduction Signal transduction through CD28 plays an important role in regulating the initial response of a T cell to antigen. Two distinct CD28 ligands, B7-1 (CD80) and B7-2 (CD86), have been identified. These ligands also bind to CTLA-4, a re- ceptor closely related to CD28 that is expressed on acti- vated T cells. Recent studies designed to examine the individual roles of B7-1 and B7-2 in the regulation of an in vivo immune response have demonstrated that costimu- lation through CD28, CTLA-4, or both is more complex than previously believed. In vivo, the costimulatory ligands B7-1 and B7-2 appear to differ in their ability to potentiate the differentiation of T helper (Th) cells into either type 1 (Thl) cells, which direct cell-mediated immunity, or type 2 (Th2) cells, which support a humoral immune response. These results have important implications for our under- standing of in vivo immune responses as well as for strate- gies of immunotherapy involving the CD28 costimuiatory pathway. The Role of Costimulatory Receptors in the Initiation of an immune Response An antigen-specific T cell immune response is initiated as a result of interaction between a T cell receptor (TCR) and antigen-major histocompatibility complex (MHC) com- plexes expressed on the surface of an antigen-presenting cell (APC). However, while TCR signal transduction is nec- essary for the activation of a naive T cell, TCR ligation alone is not sufficient to initiate an immune response under most circumstances (Figure 1). For optimal activation of a naive T cell, additional or costimulatory signals are needed. Activation through the TCR in the presence of such costimulatory signals results in T cell clonal expan- sion and in the induction of effector functions such as lymphokine production. Interaction of naive T cells with antigen in the absence of a costimulatory signal can result in T cell unresponsiveness or death. In this model, T cell costimulatory signals play a critical role in dictating the subsequent fate of a T cell that initiates a response to antigen. The BZICD28 Activation Pathway Transmits a Costimulatory Signal Work over the last several years has demonstrated that CD28 is one of the major costimulatory receptors on the surface of a resting T cell (for review see Allison, 1994). Signal transduction through CD28 synergizes with TCR signal transduction to augment both interleukin-2 (IL-2) production and proliferation of naive T cells. Blockade of the CD28 signal transduction pathway by noncross-linking monovalent antibody fragments can render T cells hypore- sponsive to subsequent challenge with antigen. Several years ago, the B cell activation antigen B7-1 (CD80) was found to be a ligand for CD28. B7-1 was subsequently found to be expressed as an activation antigen on a variety of additional APCs, including dendritic cells and mono- cytes. In addition to CD28, B7-1 can bind to the T cell activation antigen CTLA-4. CTLA-4 binds to B7-1 with -20-fold higher avidity than CD28. In contrast with°CD28, CTLA-4 is not expressed on quiescent T cells, but CTLA-4 expres- sion is detectable following TCR ligation and can be further augmented by CD28 costimulation. At present, the role of CTLA-4 in costimulation is uncertain. Depending on the circumstances, CTLA-4 has been reported to act as an additional costimulatory signal or to act as a negative sig- nal to down-mod ulate an immune response either by termi- nating a proliferative response or directly inducing apop- tosis. A soluble recombinant form of CTLA-4, CTLA41g, has been used as a competitive inhibitor of CD28 activa- tion. In vivo, CTLA41g treatment can suppress the ability to mount T cell-dependent antibody production as well as suppress the ability to mount a cell-mediated immune response against tissue grafts. The demonstration that CTLA41g could inhibit T cell- dependent immune responses that were not inhibited by B7-1 antibodies, as well as the recognition that mice defi- cient in B7-1 could still induce CD28 costimulation, re- sulted in the discovery of a second ligand for the CD28 receptor, B7-2. Although B7-2 shares only 26% amino acid identity with B7-1, B7-2 is also a member of the immuno- globulin gene superfamily and appears to be (~losely linked