Burn‐induced immunosuppression: attenuated T cell signaling independent of IFN‐γ‐ and nitric oxide‐mediated pathways

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‐γ (IFN‐γ −/− ). The results are consistent with immunosuppression attributable to burn‐induced IFN‐γ production, which in turn, drives macrophage NO synthesis (NOS). In MLR cultures, lymphocyte proliferation and IFN‐γ 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‐γ −/− splenocytes did not restore the MLR response of burned splenocytes. T cells from burned IFN‐γ −/− 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‐γ or NO production.