The B7/CD28/CTLA4 T-cell activation pathway. Implications for inflammatory lung disease.

The molecular events that modulate the T-cell response to antigen are key determinants in the outcome of pulmonary immune responses. Over the past several years, it has become evident that the B7:CD28 costimulation pathway is a critical regulator of T-cell responses both in vitro and in vivo . Given its importance in T-cell activation and its potential as a target for immune-based therapies, this perspective will review the current data on the regulation of T-cell activation by the B7 costimulatory pathway. In 1970 Bretscher and Cohn put forth the two-signal model of lymphocyte activation to explain self/nonself discrimination (1). This model proposes that T-cell activation requires two independent signals. The first is transduced through the T-cell receptor (TCR) after engagement by antigen; and the second, costimulatory signal is delivered by ligation of a distinct receptor present on the surface of the T cell. This model predicts that engagement of the TCR in the absence of costimulation will fail to activate the T cell. A substantial body of evidence has accumulated in support of this hypothesis. Early studies demonstrated that antigen presented by chemically fixed antigen-presenting cells (APCs) resulted in a failure of T-cell activation and rendered them unresponsive to further antigenic stimulation, a process termed induction of anergy. This was shown to be the result of the inability of the fixed APCs to engage costimulatory molecules, in particular CD28 (2). The anergic T cell fails to produce the autocrine growth factor interleukin-2 (IL-2) upon stimulation, and addition of exogenous IL-2 can reverse the anergic state (3). The molecular basis for costimulation remained elusive until the cloning of CD28 by Arrufo and Seed in 1987 (4). First termed Tp44, crosslinking of CD28 was initially shown to augment the proliferative response of T cells in 1984 (5). CD28 enables T cells to proliferate in the presence of the immunosuppressant cyclosporine A (6). Cytokine expression is markedly enhanced after CD28 costimulation through both transcriptional activation and posttranscriptional stabilization of messenger RNA (mRNA) (7). In addition to these effects, CD28 also regulates cell survival by induction of the anti-apoptotic protein Bcl-X L and activation of the protein kinase Akt (8). CD28 has two ligands, B7-1 (CD80) and B7-2 (CD86). B7-1 was identified as an adhesion receptor on B cells that interacted specifically with CD28 (9, 10). Subsequent work led to the identification of a second member of the B7 family, B7-2, which also bound CD28 (11–13). The greater complexity of the system became evident with the identification of an additional counter-receptor on T cells, cytotoxic T-lymphocyte antigen 4 (CTLA4), which could bind both B7-1 and B7-2 (14, 15). In contrast to CD28, CTLA4 is expressed only on activated T cells and is a negative regulator of T-cell function (16). CTLA4-deficient mice manifest massive lymphoproliferative disease, which is lethal by 3 wk of age (17, 18). Recently, new members of the B7/CD28 family have been identified. The search for new tumor necrosis factor (TNF)–inducible, nuclear factor k B (NF k B)–dependent genes led to the cloning of B7h (19). This protein shares sequence homology with both B7-1 and B7-2 but does not bind to either CD28 or CTLA4. Instead, it binds to a newly identified CD28 homolog, inducible costimulator (ICOS), which is expressed on a subset of activated T cells (20). In addition, Dong and colleagues report the cloning of another B7 homolog, B7-H1, which may be the human ortholog of B7h (21). The role of these new B7/CD28 family members in the immune response remains to be explored. The importance of CD28 in in vivo immune responses was highlighted by early studies examining transplant rejection. Blockade of B7 with CTLA4Ig, a soluble inhibitor of B7-1 and B7-2, led to prolonged graft survival after both heterotopic cardiac transplantation in rats and islet-cell xenografts in mice (22, 23). Intriguing results have also been found in the manipulation of B7:CD28:CTLA4 interactions in tumor immunity. Transfection of B7 into murine melanoma cells led to effective antitumor responses in vivo (24). Prevention of negative signaling through CTLA4 resulted in regression of primary tumors, as well as augmented secondary responses upon tumor rechallenge in mice (25). In addition to its role in the initial activation of naive T cells, recent work has examined whether CD28 influences the subsequent differentiation of CD4 1 T cells. Blockade of B7-1 in experimental autoimmune encephelomyelitis led to a reduction in disease severity and promotion of T helper (Th)2-cell development (26). In contrast, blockade ( Received in original form January 3, 2000 )