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A more recent version of this article appeared on February 1, 2008

Published online before print November 16, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0407228

Received for publication April 17, 2007.
Revised September 10, 2007.
Accepted for publication September 21, 2007.

Article

Burn-induced immunosuppression: attenuated T cell signaling independent of IFN-{gamma}- and nitric oxide-mediated pathways

Xunbao Duan *, David Yarmush *, Avrum Leeder *, Martin L. Yarmush *, and Richard N. Mitchell {dagger}@

*The Surgical Services/Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, and Shriners Hospitals for Children, Boston, Massachusetts, USA; and {dagger}Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA

@ To whom correspondence should be addressed. E-mail: rmitchell{at}rics.bwh.harvard.edu.


  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 µg/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 µg/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.

Key Words: immune suppression • T lymphocytes • antigen-presenting cells • costimulation






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