Coupling CD28 co-stimulation to immunoglobulin T-cell receptor molecules: The dynamics of T-cell proliferation and death

Immunoglobulin T-cell receptor (IgTCR) molecules are potentially potent imm une response modifiers because they allow T cells to bypass tolerance. Tole rance to self antigens has been one of the major barriers to the developmen t of effective adoptive immunotherapies for treating cancer. In vitro studi es in several laboratories have shown that cross-linking IgTCR molecules wi th the target antigen leads to cytolytic activity, cytokine release, and T- cell proliferation in model systems, However, many of these studies have us ed established T-cell lines rather than normal T cells or indirect assays o f cytotoxicity, proliferation, and cytokine release. We have sought to esta blish the validity of these model systems while developing more effective a doptive immunotherapies using normal human T cells. In the present study th e activation of T-cell proliferation after IgTCR cross-linking was evaluate d. The results show that, in addition to IgTCR signals, CD28 costimulation is required to induce expansions of normal peripheral blood mononuclear cel l-derived T cells. Signals from IgTCR alone can induce transient cell divis ion, but they do not induce the prolonged polyclonal expansions that are ch aracteristic of native immune responses. Very strong IgTCR signals could ci rcumvent the CD28 requirement, but only at levels that are unlikely to be p hysiologically relevant. CD28 costimulation also suppressed the deletion of tumor-reactive subclones by activation-induced cell death. These studies c onfirm the importance of CD28 costimulation to thr proliferation of IgTCR-m odified human T cells, a key feature of an effective, reconstructed antitum or response.