scholarly journals Breaking the co-operation between bystander T-cells and natural killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice

2015 ◽  
Vol 128 (11) ◽  
pp. 825-838 ◽  
Author(s):  
Florian Wirsdörfer ◽  
Jörg M. Bangen ◽  
Eva Pastille ◽  
Wiebke Hansen ◽  
Stefanie B. Flohé
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Muscle Injury ◽  
Adaptive Immune System ◽  
Th Cells ◽  
Skeletal Muscle Injury ◽  
Ifn Γ

Nosocomial infections represent serious complications after traumatic or surgical injuries in 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 interferon (IFN)-γ from OVA-specific Th-cells was impaired within 24 h after injury and this impairment persisted for at least 7 days. In contrast, the proliferation of OVA-specific Th-cells remained unaffected. Injury did not modulate the function of antigen-presenting cells (APCs) 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 (TLR4) and myeloid differentiation factor 88 (MyD88). In summary, upon traumatic skeletal muscle injury T-cells and NK cells together prevent the development of protective Th1 immunity. Breaking this co-operation might be a novel approach to reduce the risk of infectious complications after injury.

A role for interleukin-12/23 in the maturation of human natural killer and CD56+ T cells in vivo

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5008-5016 ◽  
Author(s):  
Sophie Guia ◽  
Céline Cognet ◽  
Ludovic de Beaucoudrey ◽  
Marlowe S. Tessmer ◽  
Emmanuelle Jouanguy ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Memory T Cells ◽  
Effector Memory ◽  
Similar Data ◽  
Effector Memory T Cells ◽  
Ifn Γ

Abstract Natural killer (NK) cells have been originally defined by their “naturally occurring” effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-γ (IFN-γ) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rβ1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-γ production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rβ1– and IL-12p40–deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56+ effector memory T cells. The susceptibility of IL-12/23 axis–deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56+ T cells in the control of these infections in humans.

scholarly journals Modelling the skeletal muscle injury recovery using in vivo contrast-enhanced micro-CT: a proof-of-concept study in a rat model

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Bruno Paun ◽  
Daniel García Leon ◽  
Alex Claveria Cabello ◽  
Roso Mares Pages ◽  
Elena de la Calle Vargas ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Rat Model ◽  
Muscle Injury ◽  
Micro Ct ◽  
Skeletal Muscle Injury ◽  
Monitoring Time ◽  
Contrast Enhanced Ct ◽  
Contrast Enhanced ◽  
Injury Recovery

Abstract Background Skeletal muscle injury characterisation during healing supports trauma prognosis. Given the potential interest of computed tomography (CT) in muscle diseases and lack of in vivo CT methodology to image skeletal muscle wound healing, we tracked skeletal muscle injury recovery using in vivo micro-CT in a rat model to obtain a predictive model. Methods Skeletal muscle injury was performed in 23 rats. Twenty animals were sorted into five groups to image lesion recovery at 2, 4, 7, 10, or 14 days after injury using contrast-enhanced micro-CT. Injury volumes were quantified using a semiautomatic image processing, and these values were used to build a prediction model. The remaining 3 rats were imaged at all monitoring time points as validation. Predictions were compared with Bland-Altman analysis. Results Optimal contrast agent dose was found to be 20 mL/kg injected at 400 μL/min. Injury volumes showed a decreasing tendency from day 0 (32.3 ± 12.0mm3, mean ± standard deviation) to day 2, 4, 7, 10, and 14 after injury (19.6 ± 12.6, 11.0 ± 6.7, 8.2 ± 7.7, 5.7 ± 3.9, and 4.5 ± 4.8 mm3, respectively). Groups with single monitoring time point did not yield significant differences with the validation group lesions. Further exponential model training with single follow-up data (R2 = 0.968) to predict injury recovery in the validation cohort gave a predictions root mean squared error of 6.8 ± 5.4 mm3. Further prediction analysis yielded a bias of 2.327. Conclusion Contrast-enhanced CT allowed in vivo tracking of skeletal muscle injury recovery in rat.

scholarly journals Early metabolic changes measured by 1H MRS in healthy and dystrophic muscle after injury

2012 ◽  
Vol 113 (5) ◽  
pp. 808-816 ◽  
Author(s):  
Su Xu ◽  
Stephen J. P. Pratt ◽  
Espen E. Spangenburg ◽  
Richard M. Lovering
Keyword(s):  
Skeletal Muscle ◽  
Muscle Injury ◽  
Tibialis Anterior Muscle ◽  
Metabolic Changes ◽  
Mdx Mice ◽  
Resonance Spectroscopy ◽  
Dystrophic Muscle ◽  
1H Mrs ◽  
Skeletal Muscle Injury

Skeletal muscle injury is often assessed by clinical findings (history, pain, tenderness, strength loss), by imaging, or by invasive techniques. The purpose of this work was to determine if in vivo proton magnetic resonance spectroscopy (1H MRS) could reveal metabolic changes in murine skeletal muscle after contraction-induced injury. We compared findings in the tibialis anterior muscle from both healthy wild-type (WT) muscles (C57BL/10 mice) and dystrophic ( mdx mice) muscles (an animal model for human Duchenne muscular dystrophy) before and after contraction-induced injury. A mild in vivo eccentric injury protocol was used due to the high susceptibility of mdx muscles to injury. As expected, mdx mice sustained a greater loss of force (81%) after injury compared with WT (42%). In the uninjured muscles, choline (Cho) levels were 47% lower in the mdx muscles compared with WT muscles. In mdx mice, taurine levels decreased 17%, and Cho levels increased 25% in injured muscles compared with uninjured mdx muscles. Intramyocellular lipids and total muscle lipid levels increased significantly after injury but only in WT. The increase in lipid was confirmed using a permeable lipophilic fluorescence dye. In summary, loss of torque after injury was associated with alterations in muscle metabolite levels that may contribute to the overall injury response in mdx mice. These results show that it is possible to obtain meaningful in vivo 1H MRS regarding skeletal muscle injury.

scholarly journals In Vivo Survival and Homeostatic Proliferation of Natural Killer Cells

2003 ◽  
Vol 197 (8) ◽  
pp. 967-976 ◽  
Author(s):  
Martin Prlic ◽  
Bruce R. Blazar ◽  
Michael A. Farrar ◽  
Stephen C. Jameson
Keyword(s):  
T Cells ◽  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Sorting ◽  
Functional Activity ◽  
Homeostatic Proliferation ◽  
Killer Cells ◽  
Bystander Cells

While the specificity and development of natural killer (NK) cells have been intensely studied, little is known about homeostasis of the mature NK population. Here we show that mouse NK cells undergo homeostatic proliferation when transferred into NK-deficient Rag−/− γC−/− hosts. Normal NK functional activity is maintained during this process, although there are some changes in NK phenotype. Using cell sorting, we demonstrate that mature (Mac-1hi) NK cells undergo homeostatic proliferation in an NK-deficient environment, yet immature (Mac-1lo) NK cells also proliferate in such hosts. We find that mature NK cells survive but do not proliferate in hosts which possess an endogenous NK pool. However, we go on to show that mature NK survival is critically dependent on interleukin (IL)-15. Surprisingly, NK survival is also compromised after transfer of cells into IL-15Rα−/− mice, implying that IL-15 responsiveness by bystander cells is critical for NK maintenance. These data imply that, similar to T cells, homeostasis of the NK pool is much more dynamic than previously appreciated and this may be relevant to manipulation of NK cells for therapeutic purposes.

Contribution of Natural Killer Cells to Inhibition of Angiogenesis by Interleukin-12

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1612-1621 ◽  
Author(s):  
Lei Yao ◽  
Cecilia Sgadari ◽  
Keizo Furuke ◽  
Eda T. Bloom ◽  
Julie Teruya-Feldstein ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Primary Cultures ◽  
Interleukin 12 ◽  
Ifn Γ

Abstract Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing interferon-γ (IFN-γ) and other downstream mediators. Here, we report that neutralization of natural killer (NK) cell function with antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10–positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK cells were locally activated. Experimental Burkitt lymphomas treated locally with IL-12 displayed tumor tissue necrosis, vascular damage, and NK-cell infiltration surrounding small vessels. After activation in vitro with IL-12, NK cells from nude mice became strongly cytotoxic for primary cultures of syngeneic aortic endothelial cells. Cytotoxicity was neutralized by antibodies to IFN-γ. These results document that NK cells are required mediators of angiogenesis inhibition by IL-12, and provide evidence that NK-cell cytotoxicity of endothelial cells is a potential mechanism by which IL-12 can suppress neovascularization.

Inflammation restraining effects of prostaglandin E2 on natural killer–dendritic cell (NK-DC) interaction are imprinted during DC maturation

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2473-2482 ◽  
Author(s):  
Catharina H. M. J. Van Elssen ◽  
Joris Vanderlocht ◽  
Tammy Oth ◽  
Birgit L. M. G. Senden-Gijsbers ◽  
Wilfred T. V. Germeraad ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
T Helper 1 ◽  
Ifn Γ ◽  
Dc Maturation

Abstract Among prostaglandins (PGs), PGE2 is abundantly expressed in various malignancies and is probably one of many factors promoting tumor growth by inhibiting tumor immune surveillance. In the current study, we report on a novel mechanism by which PGE2 inhibits in vitro natural killer–dendritic cell (NK-DC) crosstalk and thereby innate and adaptive immune responses via its effect on NK-DC crosstalk. The presence of PGE2 during IFN-γ/membrane fraction of Klebsiella pneumoniae DC maturation inhibits the production of chemokines (CCL5, CCL19, and CXCL10) and cytokines (IL-12 and IL-18), which is cAMP-dependent and imprinted during DC maturation. As a consequence, these DCs fail to attract NK cells and show a decreased capacity to trigger NK cell IFN-γ production, which in turn leads to reduced T-helper 1 polarization. In addition, the presence of PGE2 during DC maturation impairs DC-mediated augmentation of NK-cell cytotoxicity. Opposed to their inhibitory effects on peripheral blood–derived NK cells, PGE2 matured DCs induce IL-22 secretion of inflammation constraining NKp44+ NK cells present in mucosa-associated lymphoid tissue. The inhibition of NK-DC interaction is a novel regulatory property of PGE2 that is of possible relevance in dampening immune responses in vivo.

scholarly journals KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation

Blood ◽  
2005 ◽  
Vol 106 (13) ◽  
pp. 4370-4376 ◽  
Author(s):  
Sarah Cooley ◽  
Valarie McCullar ◽  
Rosanna Wangen ◽  
Tracy L. Bergemann ◽  
Stephen Spellman ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Clinical Outcomes ◽  
Hematopoietic Cell Transplantation ◽  
Cell Function ◽  
Nk Cell ◽  
Interferon Γ ◽  
Unrelated Donor ◽  
Ifn Γ

Although unrelated hematopoietic cell transplantation (HCT) is curative for many hematologic malignancies, complications and relapse remain challenging obstacles. Natural killer (NK) cells, which recover quickly after transplantation, produce cytokines and express killer immunoglobulin-like receptors (KIRs) that regulate their cytotoxicity. Some clinical trials based on a KIR ligand mismatch strategy are associated with less relapse and increased survival, but results are mixed. We hypothesized that T cells in the graft may affect NK cell function and KIR expression after unrelated transplantation and that these differences correlate with clinical outcomes. NK cell function was evaluated using 77 paired samples from the National Marrow Donor Program Research Repository. Recipient NK cells at 100 days after both unmanipulated bone marrow (UBM) and T-cell depleted (TCD) transplants were compared with NK cells from their healthy donors. NK cells expressed fewer KIRs and produced more interferon γ (IFN-γ) after UBM compared to TCD transplants. Multivariate models showed that increased NK cell IFN-γ production correlated with more acute graft-versus-host disease (GVHD), and decreased KIR expression correlated with inferior survival. These results support the notion that T cells in the graft affect NK cell reconstitution in vivo. Understanding these mechanisms may result in strategies to improve clinical outcomes from unrelated HCT.

Natural-killer cells and dendritic cells: “l'union fait la force”

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2252-2258 ◽  
Author(s):  
Thierry Walzer ◽  
Marc Dalod ◽  
Scott H. Robbins ◽  
Laurence Zitvogel ◽  
Eric Vivier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Cell Contact ◽  
Ifn Γ

AbstractSeveral recent publications have focused on the newly described interactions between natural-killer (NK) cells and dendritic cells (DCs). Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. Immature DCs appear susceptible to autologous NK-cell-mediated cytolysis while mature DCs are protected. NK-cell-induced DC activation is dependent on both tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) secretion and a cell-cell contact involving NKp30. In vitro, interleukin-12 (IL-12)/IL-18, IL-15, and IFN-α/β production by activated DCs enhance, in turn, NK-cell IFN-γ production, proliferation, and cytotoxic potential, respectively. In vivo, NK-cell/DC interactions may occur in lymphoid organs as well as in nonlymphoid tissues, and their consequences are multiple. By inducing DC activation, NK-cell activation induced by tumor cells can indirectly promote antitumoral T-cell responses. Reciprocally, DCs activated through Toll-like receptors (TLRs) induce potent NK-cell activation in antiviral responses. Thus, DCs and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, emphasizing the role of NK-cell/DC crosstalk in the coordination of innate and adaptive immune responses.

scholarly journals Functional Dichotomy in Natural Killer Cell Signaling

2001 ◽  
Vol 193 (12) ◽  
pp. 1413-1424 ◽  
Author(s):  
Francesco Colucci ◽  
Eleftheria Rosmaraki ◽  
Søren Bregenholt ◽  
Sandrine I. Samson ◽  
Vincenzo Di Bartolo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Receptors ◽  
Nk T Cells ◽  
Nk Cell Differentiation ◽  
Ifn Γ

The product of the protooncogene Vav1 participates in multiple signaling pathways and is a critical regulator of antigen–receptor signaling in B and T lymphocytes, but its role during in vivo natural killer (NK) cell differentiation is not known. Here we have studied NK cell development in Vav1−/− mice and found that, in contrast to T and NK-T cells, the absolute numbers of phenotypically mature NK cells were not reduced. Vav1−/− mice produced normal amounts of interferon (IFN)-γ in response to Listeria monocytogenes and controlled early infection but showed reduced tumor clearance in vivo. In vitro stimulation of surface receptors in Vav1−/− NK cells resulted in normal IFN-γ production but reduced tumor cell lysis. Vav1 was found to control activation of extracellular signal-regulated kinases and exocytosis of cytotoxic granules. In contrast, conjugate formation appeared to be only mildly affected, and calcium mobilization was normal in Vav1−/− NK cells. These results highlight fundamental differences between proximal signaling events in T and NK cells and suggest a functional dichotomy for Vav1 in NK cells: a role in cytotoxicity but not for IFN-γ production.

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