Breaking the cooperation between bystander T-cells and Natural Killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice

Nosocomial infections represent serious complications after traumatic or surgical injuries on intensive care units. The pathogenesis of the underlying immunosuppression is only incompletely understood. In the present study, we investigated whether injury interferes with the function of the adaptive immune system in particular with the differentiation of antigen-specific T helper (Th) cell responses in vivo. We used a mouse model for traumatic gastrocnemius muscle injury. Ovalbumin (OVA), which served as a foreign model antigen, was injected into the hind footpads for determination of the differentiation of OVA-specific Th-cells in the draining popliteal lymph node (pLN). The release of the IFN-γ from OVA-specific Th-cells was impaired within 24 h after injury, and this impairment persisted for at least 7 d. In contrast, the proliferation of OVA-specific Th-cells remained unaffected. Injury did not modulate the function of antigen-presenting cells in the pLN. Adoptive transfer of total T-cells from pLNs of injured mice inhibited IFN-γ production by OVA-specific Th-cells in naive mice. Suppressed Th1 priming did not occur in lymphocyte-deficient mice after injury but was restored by administration of T-cells before injury. Moreover, the suppression of Th1 differentiation required the presence of Natural Killer (NK) cells that were recruited to the pLN after injury; this recruitment was dependent on lymphocytes, Toll-like receptor 4, and myeloid differentiation facto...
Source: Clinical Science - Category: Biomedical Science Authors: Source Type: research

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Source: AllAfrica News: Health and Medicine - Category: African Health Source Type: news
Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially ...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
In conclusion, these findings indicate that ferroptosis, an integral process in the pathogenesis of cisplatin-induced AKI, is modulated by the expression profile of MIOX.
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
We hypothesized that the store-operated calcium entry (SOCE) channel, Orai1, participates in the activation of Th17 cells and influences renal injury. In rats, following renal ischemia/reperfusion (I/R), there was a rapid and sustained influx of Orai1+ CD4 T cells and IL-17 expression was restricted to Orai1+ cells. When kidney CD4+ cells of post–acute kidney injury (post-AKI) rats were stimulated with angiotensin II and elevated Na+ (10–7 M/170 mM) in vitro, there was an enhanced response in intracellular Ca2+ and IL-17 expression, which was blocked by SOCE inhibitors 2APB, YM58483/BTP2, or AnCoA4. In vivo, YM...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide ...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
We report that Tbx5 and Gata4 interact with opposite signs for atrial rhythm controls compared with cardiac development. Using mouse genetics, we found that AF pathophysiology caused by Tbx5 haploinsufficiency, including atrial arrhythmia susceptibility, prolonged action potential duration, and ectopic cardiomyocyte depolarizations, were all rescued by Gata4 haploinsufficiency. In contrast, Nkx2-5 haploinsufficiency showed no combinatorial effect. The molecular basis of the TBX5/GATA4 interaction included normalization of intra-cardiomyocyte calcium flux and expression of calcium channel genes Atp2a2 and Ryr2. Furthermore,...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
The interleukin 3 receptor (CD123) is a transmembrane protein that is absent or hardly expressed on normal hematopoietic stem cells, but highly expressed on the surface of cancer cells in several hematologic malignancies. In this issue of the JCI, Togami et al. investigated the mechanism of resistance to the recently approved anti-CD123 agent tagraxofusp, which consists of interleukin 3 fused to a truncated diphtheria toxin (DT) molecule. The authors demonstrated that loss of the intracellular target for DT, diphthamide, a conservative modification of histidine 715 in eukaryotic elongation factor 2, resulted in tagraxofusp...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
A strong Th17 inflammatory response aggravates ischemia reperfusion–induced (IR-induced) acute kidney injury (AKI), tissue fibrosis, and AKI-to–chronic kidney disease (CKD) progression. However, the underlying mechanisms of sustained Th17 activation following AKI and during AKI-to-CKD progression are unclear. In this issue of the JCI, Mehrotra et al. present compelling evidence that the store-operated calcium (Ca2+) channel Orai1 sustains Th17-driven inflammatory response after AKI and drives the AKI-to-CKD transition. Orai1 blockade significantly protected renal function from IR, attenuated high-salt–ind...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Here, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class II–restricted epitopes, we found that myosin heavy chain α (MYHCA) was a dominant cardiac antigen triggering post-MI CD4+ T cell activation in Balb/c mice. Transferred MYHCA614–629-specific CD4+ T cells (TCR-M cells) selectively accumulated in the myocardium and mediastinal lym...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Cardiac tissue necrosis secondary to coronary artery occlusion is one of the most common and deadly sterile injuries in developed countries. In this issue of the JCI, Rieckmann et al. identified and characterized antigen-specific CD4+ T helper (Th) cells that developed in the context of myocardial infarction (MI) in mice. They showed that myosin heavy chain α (MYHCA) is a dominant cardiac autoantigen and that T cells with T cell receptor (TCR) specificity to MYHCA acquired a Treg phenotype when adoptively transferred into infarcted mice, which mediated a cardioprotective healing response. Thus, Rieckmann et al. showe...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
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