The posttraumatic activation of CD4+ T regulatory cells is modulated by TNFR2- and TLR4-dependent pathways, but not by IL-10

Böck, Matthias; Bergmann, Christian B; Jung, Simone; Kalbitz, Miriam; Relja, Borna; Huber‐Wagner, Stefan; Biberthaler, Peter; Griensven, Martijn van; Hanschen, Marc

doi:10.1016/j.cellimm.2018.06.009

Cited by 13 publications

(19 citation statements)

References 41 publications

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“…For once, a significant plasticity between CD4+ Tregs and Th17 cells has been shown (33), meaning that T cells can convert into one another; furthermore, platelets have been shown to induce inflammation through sCD40L (26). In previous work from our group, we were able to show a tumor necrosis factor receptor 2- and toll-like receptor 4- dependent activation of CD4+ Tregs by platelets in a murine burn model (7) (Figure 5B). Taken together, while these findings cannot yet explain all the post-traumatic proceedings we discovered, these pathways should certainly be studied further in order to better understand the post-traumatic immunologic reaction.…”

Section: Discussionmentioning

confidence: 62%

“…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).…”

Section: Discussionmentioning

confidence: 82%

“…Schematic display of (A) the trauma-associated changes we were able to detect: increase in IL-17A expression on both Th17 cells and CD4+ regulatory T cells as well as increase in platelet count. (B) Some of the mechanisms possibly involved in these proceedings: a plasticity between CD4+ regulatory T cells and Th17 cells (33); reciprocal activation of CD4+ Tregs and platelets via TNF-RII- and TLR-4 dependent pathways (7); platelet derived sCD40L-dependent inflammation (26). …”

Section: Discussionmentioning

confidence: 99%

“…Hence, we were the first to show reciprocal activation of CD4+ Tregs and platelets following trauma induced injury. The pathways responsible for the modulation of CD4+ Treg activation seem to be tumor necrosis factor receptor 2- and toll-like receptor 4- dependent (7).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Background: The organism's immune response to trauma is distinctively controlled, its dysregulation leading to severe post-traumatic complications. Platelets, CD4+ regulatory T cells (CD4+ Tregs) and T helper 17 (Th17) cells have been identified to participate in the post-traumatic immune response. Unfortunately, little is known about their exact role and potential interdependency in humans. Aims of this clinical trial were to phenotype the human immune response following injury and to identify risk factors rendering the host more susceptible to trauma induced injury.Methods: This non-interventional prospective clinical trial enrolled patients following multiple trauma, follow up was conducted for 10 days. Peripheral blood CD4+ Tregs and Th17 cells were analyzed using flow cytometry to determine Interleukin 17A (IL-17A) expression. Hemostasis and platelet function were assessed with rotational thromboelastometry (ROTEM®). Subgroup analysis was conducted for the factors gender, age, and trauma severity.Results and Conclusion: This is the first clinical trial to phenotype the immune response following trauma, focusing on platelets, and the adaptive immune response. We discovered a novel increased IL-17A expression on Th17 cells and on CD4+ Tregs following trauma and describe the kinetics of the immune response. The IL-17A response on CD4+ Tregs challenges the ascribed role of CD4+ Tregs to be solely counter inflammatory in this setting. Furthermore, despite a rising number of platelets, ROTEM analysis shows post-traumatic platelet dysfunction. Subgroup analysis revealed gender, age, and trauma severity as influencing factors for several of the analyzed parameters.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Whereas TLR2 is known to serve as a costimulatory molecule in T cell activation (24--26) the relevance of TLR4 in the functionality of murine T cells is debated. A recent study shows that the activation of CD4 1 Treg after burn injury is at least partially dependent on TLR4, but it is unknown whether intrinsic TLR4 signaling in Treg is involved (27). In this study, we demonstrate that TLR4-dependent CD8 T cell activation after skeletal muscle injury occurred in trans through IL-12p40, the common subunit of bioactive IL-12 and IL-23.…”

Section: Discussionmentioning

confidence: 49%

TLR4 Transactivates CD8+ T Lymphocytes upon Acute Sterile Tissue Injury

et al. 2021

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Acute major tissue injury induces immune dysregulation that is characterized by the development of systemic sterile inflammation and an increased risk for opportunistic infections. Although the contribution of the innate immune system has been examined in detail, research on the impact of acute sterile tissue damage on the T cell compartment remains limited. In the current study, we used a clinically relevant mouse model for traumatic skeletal muscle injury to investigate the impact of sterile tissue damage on diverse subpopulations of CD4 + Th and CD8 + cytotoxic T cells in systemic and local lymphoid organs. For the first time, to our knowledge, we provide evidence that injury selectively induced the expression of the activation marker CD69 on naive and central/virtual memory CD8 + T cells in the lymph nodes but not in the spleen of male mice. CD4 + Th cells remained unaffected in both organs. The activation of CD8 + T cells was dependent on signaling through TLR4. Within a few hours, injury triggered the expression of IL-12 in the lymph nodes in a TLR4-dependent manner. Blocking of IL-12 prevented the activation of naive and central memory CD8 + T cells after injury. Thus, early after traumatic tissue damage, TLR4 transactivates naive and central/virtual memory CD8 + T cells through innate cytokines in local lymph nodes, where they might modulate forthcoming local immune responses.

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Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways

et al. 2021

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CD4+FoxP3+ regulatory T cells (CD4+ Tregs) are known to dampen inflammation following severe trauma. Platelets were shown to augment their posttraumatic activation in burn injury, but the exact mechanisms remain unclear. We hypothesized that platelet activation mechanisms via GPIIb/IIIa, fibrinogen, and PAR4 have an immunological effect and modulate CD4+ Treg activation early after trauma. Therefore, C57Bl/6 N mice were injected with tirofiban (GPIIb/IIIa inhibition), ancrod (fibrinogen splitting enzyme), or tcY-NH2 (selective PAR4 antagonist peptide) before inducing a third-degree burn injury of 25% of the total body surface area. Changes in coagulation, and local and systemic CD4+ Treg activity were assessed via rotational thromboelastometry (ROTEM®) and phospho-flow cytometry 1 h post intervention. The inhibition of GPIIb/IIIa and fibrinogen locally led to a higher basic activity of CD4+ Tregs compared to non-inhibited animals. In contrast, PAR4 disruption on platelets locally led to an increased posttraumatic activation of CD4+ Tregs. Fibrinogen led to complete elimination of coagulation, whereas GPIIb/IIIa or PAR4 inhibition did not. GPIIb/IIIa receptor and fibrinogen inhibition increase CD4+ Tregs activity independently of trauma. Both are crucial for thrombus formation. We suggest platelets trapped in thrombi are unable to interact with CD4+ Tregs but augment their activity when circulating freely. In contrast, PAR4 seems to reduce CD4+ Treg activation following trauma. In summary, GPIIb/IIIa-, PAR4-, and fibrinogen-dependent pathways in platelets modulate CD4+ Treg baseline activity, independently from their hemostatic functionality. PAR4-dependent pathways modulate the posttraumatic interplay of platelets and CD4+ Tregs.

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The posttraumatic activation of CD4+ T regulatory cells is modulated by TNFR2- and TLR4-dependent pathways, but not by IL-10

Cited by 13 publications

References 41 publications

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

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

TLR4 Transactivates CD8+ T Lymphocytes upon Acute Sterile Tissue Injury

Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways

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