scholarly journals Central nervous system (CNS)–resident natural killer cells suppress Th17 responses and CNS autoimmune pathology

2010 ◽  
Vol 207 (9) ◽  
pp. 1907-1921 ◽  
Author(s):  
Junwei Hao ◽  
Ruolan Liu ◽  
Wenhua Piao ◽  
Qinghua Zhou ◽  
Timothy L. Vollmer ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Specific Activity ◽  
Cns Inflammation ◽  
Selective Blockade ◽  
Autoimmune Pathology ◽  
Organ Specific

Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention.

scholarly journals TGF-β in Mice Ameliorates Experimental Autoimmune Encephalomyelitis in Regulating NK Cell Activity

2019 ◽  
Vol 28 (9-10) ◽  
pp. 1155-1160 ◽  
Author(s):  
J. Xu ◽  
Y. Wang ◽  
H. Jiang ◽  
M. Sun ◽  
J. Gao ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Nk Cells ◽  
Nk Cell ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Multiple sclerosis is a disease characterized by inflammation and demyelination located in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is the most common animal model for multiple sclerosis (MS). Although the roles of T cells in MS/EAE have been well investigated, little is known about the functions of other immune cells in the neuroinflammation model. Here we found that an essential cytokine transforming growth factor β (TGF-β) which could mediate the differentiation of Th17/regulatory T cells was implicated in the natural killer (NK) cells’ activity in EAE. In EAE mice, TGF-β expression was first increased at the onset and then decreased at the peak, but the expressions of TGF-β receptors and downstream molecules were not affected in EAE. When we immunized the mice with MOG antigen, it was revealed that TGF-β treatment reduced susceptibility to EAE with a lower clinical score than the control mice without TGF-β. Consistently, inflammatory cytokine production was reduced in the TGF-β treated group, especially with downregulated pathogenic interleukin-17 in the central nervous system tissue. Furthermore, TGF-β could increase the transcription level of NK cell marker NCR1 both in the spleen and in the CNS without changing other T cell markers. Meanwhile TGF-β promoted the proliferation of NK cell proliferation. Taken together, our data demonstrated that TGF-β could confer protection against EAE model in mice through NK cells, which would be useful for the clinical therapy of MS.

scholarly journals Natural Killer Cells Utilize both Perforin and Gamma Interferon To Regulate Murine Cytomegalovirus Infection in the Spleen and Liver

2005 ◽  
Vol 79 (1) ◽  
pp. 661-667 ◽  
Author(s):  
Joy Loh ◽  
Dortha T. Chu ◽  
Andrew K. O'Guin ◽  
Wayne M. Yokoyama ◽  
Herbert W. Virgin
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Acute Phase ◽  
Nk Cell ◽  
Gamma Interferon ◽  
Murine Cytomegalovirus ◽  
Mcmv Infection ◽  
Independent Manner ◽  
Organ Specific ◽  
Ifn Γ

ABSTRACT Natural killer (NK) cells are critical for innate regulation of the acute phase of murine cytomegalovirus (MCMV) infection and have been reported to utilize perforin (Pfp)- and gamma interferon (IFN-γ)-dependent effector mechanisms in an organ-specific manner to regulate MCMV infection in the spleen and liver. In this study, we further examined the roles of NK cells, Pfp, and IFN-γ in innate immunity to MCMV infection. With the recently described NK cell-deficient (NKD) mouse, we confirmed previous findings that NK cells, but not NKT cells, are required for control of the acute phase of MCMV infection in spleen and liver cells. Interestingly, we found that Pfp and IFN-γ are each important for regulating MCMV replication in both the spleen and the liver. Moreover, NK cells can regulate MCMV infection in the spleens and livers of Pfp−/− mice in a Pfp-independent manner and can use an IFN-γ-independent mechanism to control MCMV infection in IFN-γ−/− mice. Thus, contrary to previous reports, NK cells utilize both Pfp and IFN-γ to control MCMV infection in the spleen and liver.

scholarly journals The Clinical Course of Experimental Autoimmune Encephalomyelitis and Inflammation Is Controlled by the Expression of Cd40 within the Central Nervous System

2001 ◽  
Vol 193 (8) ◽  
pp. 967-974 ◽  
Author(s):  
Burkhard Becher ◽  
Brigit G. Durell ◽  
Amy V. Miga ◽  
William F. Hickey ◽  
Randolph J. Noelle
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Cell ◽  
Chimeric Mice ◽  
Autoimmune Encephalomyelitis ◽  
Cns Inflammation ◽  
Organ Specific ◽  
The Central Nervous System ◽  
Experimental Autoimmune

Although it is clear that the function of CD40 on peripheral hematopoietic cells is pivotal to the development of autoimmunity, the function of CD40 in autoimmune disease outside this compartment is unresolved. In a model of experimental autoimmune encephalomyelitis (EAE), evidence is presented that CD40–CD154 interactions within the central nervous system (CNS) are critical determinants of disease development and progression. Using bone marrow (BM) chimeric mice, the data suggest that the lack of expression of CD40 by CNS-resident cells diminishes the intensity and duration of myelin oligodendrocyte glycoprotein (MOG)-induced EAE and also reduces the degree of inflammatory cell infiltrates into the CNS. Although CNS inflammation is compromised in the CD40+/+→CD40−/− BM chimeric mice, the restricted CD40 expression had no impact on peripheral T cell priming or recall responses. Analysis of RNA expression levels within the CNS demonstrated that encephalitogenic T cells, which entered a CNS environment in which CD40 was absent from parenchymal microglia, could not elicit the expression of chemokines within the CNS. These data provide evidence that CD40 functions outside of the systemic immune compartment to amplify organ-specific autoimmunity.

The Regulation Of Central Nervous System Acute Lymphoblastic Leukemia By Natural Killer Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1393-1393
Author(s):  
Liron Frishman-Levy ◽  
Avishai Shemesh ◽  
Shahar Frenkel ◽  
Allan Bar-Sinai ◽  
Zhenya Ni ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Nk Cells ◽  
Natural Killer ◽  
Lymphoblastic Leukemia ◽  
Scid Mice ◽  
Leukemia Cells ◽  
Adequate Treatment ◽  
Nsg Mice

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy accounting for 80% of leukemias. The involvement of the central nervous system (CNS) by ALL is a major clinical problem and occurs in about 50% of the children without adequate treatment. The introduction of CNS-directed therapy consisting of intrathecal and high dose systemic chemotherapy and, occasionally, cranial irradiation, reduced relapse rate to less than 5% and has become a prerequisite for treating children with ALL. However, substantial neurotoxicity associated with this therapy is a major concern. Moreover the CNS is involved in up to a third from all relapses. To date very little is known about the pathogenesis of CNS leukemia. Our research was promoted by the previous observation that high mRNA expression of interleukin 15 (IL15) in leukemic blasts is associated with increased risk for CNS involvement (Cario et al JCO 2007;25:4813-20). As IL15 is a strong stimulant of Natural Killer (NK) cells, we hypothesized that the increased expression of IL15 may activate NK cells which, in turn, will control residual ALL cells in the peripheral blood but not in the relatively protected central nervous system. To investigate this hypothesis, we utilized two mouse models, a S49-derived T lymphoblastic leukemia syngeneic model and a novel human xenograft ALL model in immune-deficient mice. We found that constitutive expression of IL15 in mouse T lymphoblastic leukemia cells transplanted in neonatal Balb/c mice markedly slowed the development of systemic disease and caused CNS leukemia characterized by pronounced clinical CNS symptoms and subarachnoid infiltration of leukemia cells. This phenotype was accompanied by increase in activated natural killer (NK) cells (from 0.16% to 18.6% P<0.01). Similarly, we demonstrated that transplantation of the human B-cell precursor ALL line 018Z cause isolated CNS leukemia in NOD/SCID mice but induced aggressive systemic and CNS leukemia in NK-deficient NOD scid Il2rg null (NSG) mice. We further found that 018Z cells express and secrete endogenous IL15 and activated NK cells in-vivo in NOD/SCID mice. Remarkably, transplantation of 018Z cells in NOD/SCID mice after antibody mediated depletion of NK cells, resulted in a combined peripheral and CNS leukemia as observed in NSG mice. Mechanistic studies showed that 018Z leukemic blasts are efficiently killed by primary human NK cells and highly express ligands for the NKG2D and the NKp44 activating receptors. Blocking of the NKG2D receptor significantly reduced killing by NK cells. Taken together we show here, for the first time, a crucial role for NK cells in the control of CNS leukemia. We suggest that the association between IL15 expression in ALL blasts and isolated CNS relapse might be explained by activation of NK cells leading to increased surveillance of residual leukemia in the bone marrow but not in the CNS which serve as a sanctuary site for tumor growth. Disclosures: No relevant conflicts of interest to declare.

CHAPTER 9: Immunology of TBEV-Infections

2020 ◽  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Sample Collection ◽  
Tick Borne Encephalitis ◽  
Viral Infectious Disease ◽  
The Central Nervous System

Tick-borne encephalitis (TBE) is a viral infectious disease of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is usually a biphasic disease and in humans the virus can only be detected during the first (unspecific) phase of the disease. Pathogenesis of TBE is not well understood, but both direct viral effects and immune-mediated tissue damage of the central nervous system may contribute to the natural course of TBE. The effect of TBEV on the innate immune system has mainly been studied in vitro and in mouse models. Characterization of human immune responses to TBEV is primarily conducted in peripheral blood and cerebrospinal fluid, due to the inaccessibility of brain tissue for sample collection. Natural killer (NK) cells and T cells are activated during the second (meningo-encephalitic) phase of TBE. The potential involvement of other cell types has not been examined to date. Immune cells from peripheral blood, in particular neutrophils, T cells, B cells and NK cells, infiltrate into the cerebrospinal fluid of TBE patients.

scholarly journals Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

2021 ◽  
Author(s):  
Leoni Rolfes ◽  
Tobias Ruck ◽  
Christina David ◽  
Stine Mencl ◽  
Stefanie Bock ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Neurological Deficits ◽  
In Vitro Assays ◽  
Experimental Stroke ◽  
Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

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