NKT cells have been described as innate regulatory cells because of their rapid response to conserved glycolipids presented on CD1d via their invariant TCR. However, little is known about the contribution of the hepatic NKT cell to the development of a local and/or systemic immune response to acute septic challenge (cecal ligation and puncture (CLP)). We found not only that mice deficient in invariant NKT cells (Jα18−/−) had a marked attenuation in CLP-induced mortality, but also exhibited an oblation of the systemic inflammatory response (with little effect on splenic/peritoneal immune responsiveness). Flow cytometric data indicated that following CLP, there was a marked decline in the percentage of CD3+α-galactosylceramide CD1d tetramer+ cells in the mouse C57BL/6J and BALB/c liver nonparenchymal cell population. This was associated with the marked activation of these cells (increased expression of CD69 and CD25) as well as a rise in the frequency of NKT cells positive for both Th1 and Th2 intracellular cytokines. In this respect, when mice were pretreated in vivo with anti-CD1d-blocking Ab, we observed not only that this inhibited the systemic rise of IL-6 and IL-10 levels in septic mice and improved overall septic survival, but that the CLP-induced changes in liver macrophage IL-6 and IL-10 expressions were inversely effected by this treatment. Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute septic shock.
The National Emergency X-Radiography Utilization Study definition of a distracting injury may be narrowed. Upper torso injuries may be sufficiently painful to distract from a reliable cervical spine examination. Patients may detect spine tenderness in the presence of isolated painful lower torso injuries. Patients with spine tenderness warrant imaging.
Introduction:Burn injury results in early T cell apoptosis, lymphopenia and associated T cell dysfunction. Subsequent reconstitution of the T cell compartment late after burn injury via homeostatic proliferation generates hyper-responsive memory CD8ϩ T cells of unclear functional significance. In this study, we hypothesized that the hyper-responsive CD8ϩ population isolated late after burn injury 1) has enhanced activity in vivo and 2) that burn injury associated apoptosis is necessary for the generation and hyperresponsiveness of this unique T cell population. Methods: To test these hypotheses, we used a mouse model of allogeneic skin graft rejection to assess in vivo activity and the glucocortocoid receptor inhibitor mifepristone (RU486) to block burn associated apoptosis. Female C57Bl/6 (B6) mice transgenic for the T cell receptor recognizing the male minor histocompatibility antigen HY (HY TCR mice) were anesthetized and treated as follows (nϭ6 per group): 1) 20% TBSA burn; 2) 20% TBSA burn and 3 daily injections (20g/g) of RU486; 3) sham and 4) sham with RU486. Mice were sacrificed 14 days after burn injury, splenic CD8ϩ T cells purified (Ͼ95% purity) by magnetic cell separation and CD8ϩ T cells from each group were adoptively transferred i/v into female wildtype B6 mice (1ϫ106 cells / mouse, nϭ6 per group). Transferred cells were allowed to redistribute for 48 hours, then each mouse received allogeneic male (HYϩ) skin and control isogeneic female (HYϪ) tail skin grafts. Grafts were monitored daily, scored for rejection and median survival times of allogeneic male grafts were calculated. Statistical analysis was performed by logrank test with significance defined as pϽ0.05. Results: Mice that received CD8ϩ HY TCR T cells isolated late after burn injury rejected male skin graft significantly faster than mice that received CD8ϩ T cells from sham mice (11 days versus 15 days, pϭ0.038), demonstrating that transferred cells from burn mice have enhanced activity in vivo. This effect was blocked when RU486 was administered to burn mice and subsequent skin graft rejection in adoptive transfer recipients was compared to the burn alone recipients (19 days versus 11 days, pϭ0.0013). Administration of RU486 to burn mice also resulted in similar graft rejection when compared to sham (19 days versus 15 days, pϭ0.30), sham with RU486 (19 days versus 15 days, pϭ0.55) and no cells (19 days versus 17 days, pϭ0.75) adoptive transfer recipients. Conclusions: This study demonstrates for the first time the functional significance in vivo of hyper-responsive CD8ϩ T cells late after burn injury. While blocking apoptosis may have beneficial effects on immune function early after burn injury it also appears to prevent the development of these hyper-responsive memory T cells. These data provide a mechanism for allograft rejection in the face of generalized immune dysfunction as well as insight into the mechanism of dynamic T cell dysfunction following burn injury.
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