Negative signaling contributes to T-cell anergy in trauma... : Critical Care Medicine (original) (raw)

Clinical Investigations

Bandyopadhyay, Gautam PhD; De, Asit PhD; Laudanski, Krzysztof MD; Li, Fang MD; Lentz, Christopher MD; Bankey, Paul MD, PhD; Miller-Graziano, Carol PhD

From the University of Rochester Medical Center, Department of Surgery, Rochester, NY.

Supported, in part, by research grant GM65237 from the National Institute of General Medical Sciences (CLMG).

The authors have not disclosed any potential conflicts of interest.

Abstract

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 posttrauma 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 CD3ε. 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.