Negative Signaling Contributes To T-Cell Anergy In Trauma Patients

Objective: Maintenance of postinjury T-lymphocyte immune paralysis or anergy could result from failure to activate costimulatory receptors during T-cell receptor activation and/or from chronic stimulation of a competing set of elevated corepressor receptors. Our objective was to assess whether elevated post-trauma T-lymphocyte surface expression of corepressor receptors was associated with immunodepressed lymphocyte responses and corresponded to increased inhibitory and decreased activating signal transduction molecules.Design: Prospective observational study.Setting., University trauma intensive care unit and research laboratory.Patients: Sixty-one severe thermal and mechanical trauma patients.Interventions: None.Measurements and Main Results., Isolated trauma patients' and controls' peripheral blood T cells were assayed for negative and positive costimulation receptor expression. These receptor expression levels were compared (flow cytometry) between the two groups and correlated to T-cell levels of inhibitory and activating signal transduction molecules and proliferation capacity. Patients' proliferation hyporesponsive (anergic) T cells had increased expression of novel inhibitory receptors (corepressors) PD-1 (p <.05) and CD47 (p <.05) vs. patients' T-cell proliferation competent or controls' T cells. Patients' T-cell CD152 (CTLA-4) expression was also elevated vs. controls. Only patients' anergic T cells had simultaneously increased levels of the inhibitory signal transduction proteins, c-Cbl, a ubiquitin-ligase (p <.01) and SHP-1, a phosphatase (p <.01), concomitant to depressed phosphorylation of the activating signal kinases Erk, Zap70, and CD3 epsilon. T-cell receptor complex phosphorylation and activation of the interleukin-2 pivotal transcriptional complex protein CREB were also simultaneously depressed as c-Cbl and SHP-1 were elevated.Conclusions: Up-regulated corepressor receptor expression is novelly shown to characterize trauma patients' anergic T cells and correlate with predominance of inhibitory overactivating signal transduction molecules during T-cell stimulation. This could contribute to postinjury immunosuppression.