title: Negative signaling contributes to T-cell anergy in trauma patients.
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.
  
  
  METHODS
  Prospective observational study.
  
  
  METHODS
  University trauma intensive care unit and research laboratory.
  
  
  METHODS
  Sixty-one severe thermal and mechanical trauma patients.
  
  
  METHODS
  None.
  
  
  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 CD3Euro. 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.
authors.affiliation: University of Rochester Medical Center, Department of Surgery, Rochester, NY, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: Asit
authors.initials: A
authors.lastname: De
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Laudanski
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Christopher
authors.initials: C
authors.lastname: Lentz
authors.forename: Paul
authors.initials: P
authors.lastname: Bankey
authors.forename: Carol
authors.initials: C
authors.lastname: Miller-Graziano
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000097:blood; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002056:Burns / Q000276:immunology*; D051928:CD47 Antigen / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000097:blood; D060908:CTLA-4 Antigen; D017635:Clonal Anergy / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007362:Intensive Care Units; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor; D011446:Prospective Studies; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000097:blood; D011505:Protein-Tyrosine Kinases / Q000097:blood; D050721:Proto-Oncogene Proteins c-cbl / Q000097:blood; D012318:RNA Polymerase I; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D014947:Wounds and Injuries / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000097:blood
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D051928:CD47 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; C119975:POLR1G protein, human; D012318:RNA Polymerase I; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C067419:CBL protein, human