Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation.

Abstract

The maximal T-cell response to its antigen requires presentation of the antigen by a major histocompatibility complex class II molecule as well as the delivery of one or more costimulatory signals provided by the antigenpresenting cell (APC). Although a number of candidate molecules have been identified that are capable of delivering a costimulatory signal, increasing evidence suggests that one such critical pathway involves the interaction of the T-cell surface antigen CD28 with its ligand B7, expressed on APCs.In view of the number of potential costimulatory molecules that might be expressed on the cell surface of APCs, artificial APCs were constructed by stable transfection of NIM 3T3 cells with HLA-DR7, B7, or both. Here, we show that in a human antigen-specific model system, when tetanus toxoid peptide antigen is presented by cells cotransfected with HLA-DR7 and B7, optimal T-cell proliferation and interleukin 2 production result. In contrast, antigen presentation, in the absence of B7 costimulation, results in T-cell clonal anergy. These results demonstrate that it is possible to induce antigen-specific clonal tolerance in human T cells that have been previously sensitized to antigen. The artificial antigen-presenting system provides a useful model for the investigation of the biochemical events involved in the generation of tolerance and for the study of signals necessary to overcome tolerance.The maximal T-cell response to its antigen requires presentation of the antigen by a major histocompatibility complex (MHC) class II molecule and the delivery of one or more costimulatory signals provided by heterotypic adhesion between receptor ligand pairs on the T cell and the antigenpresenting cell (APC) (1-3). Signaling through the T-cell receptor (TCR) complex alone can result in a downregulatory signal for human T-cell growth (4, 5). In vitro systems in the mouse have demonstrated that in the absence of a costimulatory signal, occupancy of the TCR by peptide fragments in the context of MHC class II is capable of inducing a long-lasting antigen-specific unresponsiveness, termed anergy (1, 3, 6). Increasing in vitro evidence in murine and human systems suggests that one such critical costimulatory pathway involves the interaction of the T-cell surface antigen CD28 with its ligand B7 on the APC (7-10). CD28 is constitutively expressed on 95% of resting CD4+ and 50% of CD8+ human T lymphocytes (11,12). After T-cell activation, CTLA4, a second higher-affinity ligand for B7 (13), is expressed and CD28 expression increases. B7 expression is limited to cells capable of presenting antigen, including activated B cells (14), activated monocytes (15), and dendritic cells (16). After T-cell activation, ligation of CD28 by anti-CD28 monoclonal antibody (mAb) or by B7 induces maximal proliferation and interleukin 2 (IL-2) secretion (7,8,17,18). Two recent studies in murine systems suggest that the inhibition of the CD28-B7The publication costs of this article were defrayed in part by page charge payment. This articl...

Efficient infection of primitive hematopoietic stem cells by modified adenovirus

“…IL2 is mainly produced by T cells during their activation and enhances their own expansion. 20,21 Production of IL2 is diminished in many patients with cancer due to T cell anergy [45][46][47] and several phase I studies [23][24][25][26]48 have shown that administration of Ad5-IL2 gene-modified tumor cells can induce specific antitumor responses mediated by T cells. Although successful in these studies in solid tumors, Ad5-IL2 is limited in gene therapy of hematopoietic malignancies by its low efficacy of infection and by a high toxicity.…”

B7 Costimulation and Intracellular Indoleamine 2,3-Dioxygenase Expression in Umbilical Cord Blood and Adult Peripheral Blood

“…Both the TCR and CD28 are constitutively expressed by most naïve T cells, enabling them to respond to the antigen being presented [1]. Without costimulation, the signal from the TCR induces the tolerance of T cells to their cognate antigen, instead of being activated [2].…”

Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

“…[5][6] In contrast, blockade of this pathway results in the induction of antigen-specific unresponsiveness, or anergy, both in vitro and in vivo. 7,8 However, several other T cell-APC interactions can also provide costimulation. One such interaction is mediated by cytotoxic T-lymphocyte antigen-4 (CTLA-4), which is structurally related to CD28, but it inhibits rather than enhances T-cell activation.…”