Platelets modulate the immune response following trauma by interaction with CD4+ T regulatory cells in a mouse model

Abstract

CD4+ T regulatory cells (Tregs) play a pivotal role in the anti-inflammatory immune response following trauma. The mechanisms of CD4+ Treg activation are mostly unknown. Here, we hypothesize that platelets regulate CD4+ Treg activation following trauma. In a murine burn injury model (male C57Bl/6N mice), depletion of platelets or CD4+ Tregs was conducted. Draining lymph nodes, blood and spleen were harvested 2 h and 7 days after trauma. CD4+ Treg activation was measured using phospho- and conventional flow cytometry. Platelet activation was analyzed using thromboelastometry and flow cytometry. Trauma differentially activates CD4+ T cells, early after trauma only CD4+ Tregs are activated. Following burn injury, platelets augment the activation of CD4+ Tregs. This effect could only be seen early after trauma. While CD4+ Tregs influence hemostasis early following trauma, platelet activation markers were unchanged. Beyond their role in hemostasis, platelets are able to modulate the immunologic host response to trauma-induced injury by augmenting the activation of CD4+ Tregs. CD4+ Treg activation following trauma is considered protective. In addition, CD4+ Tregs are capable of modulating the hemostatic function of platelets. For the first time, we could show reciprocal activation of platelets and CD4+ Tregs as part of the protective immune response following trauma.

Trauma Induces Interleukin-17A Expression on Th17 Cells and CD4+ Regulatory T Cells as Well as Platelet Dysfunction

“…CD4+ Tregs have been shown to be activated early after injury in a murine burn model (46). Furthermore, also using the murine burn model, we have earlier been able to demonstrate an interaction of CD4+ Tregs with platelets, this interaction being modulated by TNF-RII- and TLR4-dependent pathways (6, 7). In this study, regarding CD4+ Treg count, we saw an increasing number relative to all CD4+ lymphocytes during the observed time period (Figure 2A).…”

“…The detection of an interaction of CD4+ CD4+ Tregs with platelets in a murine burn model led us to investigate platelet function in this study on multiple trauma patients as well (6). Our thromboelastometric results show an increasing MCF both in the extem and fibtem measurements (Figures 4B,C); however, subtracting the fibtem MCF from the extem MCF, thereby calculating the platelet contribution or platelet MCF (41), we actually saw a decrease (Figure 4D).…”

“…A decreased CD4+ Treg/Th17 cell ratio was recently discovered in a multiple trauma rat model, correlating inversely with disease activity (5). In our previous studies utilizing a murine burn injury model, we have been able to show impaired activation of intracellular pathway signaling in CD4+ Tregs after platelet depletion (6). Hence, we were the first to show reciprocal activation of CD4+ Tregs and platelets following trauma induced injury.…”

Role of Platelets in Leukocyte Recruitment and Resolution of Inflammation

“…Platelets have been previously described to interact with regulatory T cells under inflammatory conditions. In this context, it could be shown that platelets are needed to control the anti-inflammatory actions of CD4 + regulatory T cells following burn injury trauma in mice ( 156 ). In another organ, platelets have also been shown to interact with CD4 + T cells in the liver following ischemic injury and during atherosclerosis ( 157 , 158 ).…”

Platelets in Inflammation and Resolution

“…Interestingly, platelets have antiinflammatory properties. Platelets are known to interact with and enhance responses of regulatory T cells, resulting in increased IL-10 levels (142,143). Regulatory T cells are needed to support macrophage efferocytosis via secretion of IL-13 during resolution of inflammation (144).…”