title: Burn-induced immunosuppression: attenuated T cell signaling independent of IFN-gamma- and nitric oxide-mediated pathways.
abstract: Burn injury results in immunosuppression; previous work implicated a combination of altered T lymphocyte subpopulations and the elaboration of macrophage-derived mediators. However, the conclusions were based on T cell stimulations in the setting of high-dose polyclonal mitogenic stimuli and a single kinetic time-point. In this study, splenocytes from burned animals were used to examine lymphocyte responses over a multi-day time course following saturating and subsaturating anti-CD3, as well as mixed lymphocyte response (MLR) stimulation. Burn injury resulted in suppressed splenocyte-proliferative responses to high-dose anti-CD3 (2 microg/ml) at all culture time-points (Days 2-5); this inhibition was eliminated by removing macrophages from the splenocyte cultures, by blocking NO production, or by using splenocytes from burned animals congenitally deficient in IFN-gamma (IFN-gamma(-/-)). The results are consistent with immunosuppression attributable to burn-induced IFN-gamma production, which in turn, drives macrophage NO synthesis (NOS). In MLR cultures, lymphocyte proliferation and IFN-gamma production were depressed at later time-points (Days 3-5). APC from burned animals showed no defects as MLR stimulators; T cells from burned animals showed defective, proliferative responses, regardless of the stimulator population. Removing macrophages, adding a NOS inhibitor, or using IFN-gamma(-/-) splenocytes did not restore the MLR response of burned splenocytes. T cells from burned IFN-gamma(-/-) animals also showed depressed proliferation with subsaturating levels of anti-CD3 (0.1 microg/ml); anti-CD-28 augmented the proliferative response. We conclude that burn-induced immunosuppression to authentic antigenic stimulation is related at least in part to defective CD3 signaling pathways and not simply to increased IFN-gamma or NO production.
authors.affiliation: The Surgical Services/Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Xunbao
authors.initials: X
authors.lastname: Duan
authors.forename: David
authors.initials: D
authors.lastname: Yarmush
authors.forename: Avrum
authors.initials: A
authors.lastname: Leeder
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.forename: Richard N
authors.initials: RN
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation; D002056:Burns / Q000276:immunology* / Q000503:physiopathology; D017252:CD3 Complex / Q000276:immunology*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000172:deficiency / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D009569:Nitric Oxide; D007371:Interferon-gamma