In our present study, we generated a cohort of trauma patients that was homogeneous in terms of sex, age, severity of injury, and mode of injury. Additionally, we concurrently investigated cells in the innate and adaptive arms of the immune system in this cohort of patients by determining the cell absolute numbers as well as function. Further, the mechanism underlying the function was determined. We believe that the combination of these three aspects make this a unique study.
In general, the immunological response to trauma has been modeled as a systemic inflammatory response followed sequentially by compensatory anti-inflammatory response. In our study, one aspect of SIRS, the increase in neutrophil priming and numbers, was observed up to 96 hours following trauma. One characteristic of CARS is reduced T cell numbers and impaired immune function. We also observed this phenomenon. However, this was seen almost immediately and up to 96 hours following trauma. Thus, aspects of SIRS and CARS were seen concurrently for a fairly prolonged period of time. Altogether, we believe that presence of both hyperactive neutrophils and anergic T cells needs to be considered when attempting to modulate the immune system following trauma so to beneficially modulate the subsequent response to adverse clinical events such as acute respiratory distress syndrome (ARDS), VAP and opportunistic infections.
This and previous studies  have demonstrated that trauma can lead to a decrease in the T cell numbers. While possible reasons for this decline include the effects from transfusion, dilution from resuscitation and movement from periphery, based on numerous studies, we feel apoptosis is the underlying cause of the decline [20, 21]. The end result of massive naïve T cell apoptosis would include immunosuppression due to a loss of the TCR repertoire able to respond to subsequent infections, along with production of anti-inflammatory mediators by macrophages during phagocytosis of apoptotic bodies . Further, the loss of T cell-mediated IFN-γ production serves to limit the activation of the innate immune system.
Initial events in TCR-mediated activation can have profound effects on T cell function. Within the TCR/CD3 complex are ITAMS which become phosphorylated during antigen-driven T cell activation. However, the degree of phosphorylation determines the degree of T cell activation. For example, a single ITAM phosphorylation activates SHP . SHP expression is increased following trauma and its actions are known to be inhibitory . Yet, two ITAM phosphorylations will result in full T cell activation . Thus, we believe the differences observed in CD247 phosphorylation are, in part, responsible for the differences in IFN-γ production. Whether these differences are due to increased phosphatase activity or decreased gene expression is currently under investigation.
The T cell specific studies indicate that of the patients tested for IFN-γ production and CD247 phosphorylation, there were two fairly distinct groups. When compared to healthy controls, one group showed no significant differences in IFN-γ production and CD247 phosphorylation, while the other group showed significant decreases in each. Both groups had no significant differences in injury severity scores (25 versus 21, respectively) or age (32.4 versus 31.5 years, respectively). However, the hospital length of stay was trending towards an increase for those patients with poor T cell function (20.8 versus 12.3 days, p = 0.08). Whether or not these assays will be more predictive of adverse clinical events is an ongoing investigation.
Our data show that the function and numbers of neutrophils are increased following blunt trauma (Figure 1). Associated with this is increased phosphorylated Akt (Figure 3b). Active Akt is known to both decrease apoptosis as well as increase the oxidative burst [25, 26]. The excessive number of these hyperactive cells can lead to excessive tissue damage, further worsening the condition of some trauma patients. Additionally, it has been shown that phosphorylated Akt can be prognostic for poor clinical outcomes . We hypothesize that Akt has increased phosphorylation due to increased systemic IL-6 observed following trauma. Increased IL-6 can lead to increased tyrosine kinase activity by Jak-1 and -2 . A potential tyrosine phosphorylation target of Jak-2 is PP2a . When tyrosine-307 is phosphorylated, PP2a assembly as well as activity might selectively be inhibited . This is important, as Akt is known to be de-phosphorylated by PP2a (reviewed in ). Although other mediators can activate Jak2, we believe IL-6 represents a likely candidate for future studies.
Although this study demonstrates new insights regarding the response of human T-cells to blunt trauma, it has limitations. First, we may not be measuring the whole of the immune compartment through our current methodology. For example, T cell numbers were not measured in the thymus, spleen or lymph nodes. Secondly, blunt trauma is wide-ranging and the effect of different mechanisms may play a role in the changes seen in this study. Even patients with non-significant differences in injury severity scores can have vastly different outcomes based on mechanism.