scholarly journals CD4 T Cells Contribute to Virus Control and Pathology following Central Nervous System Infection with Neurotropic Mouse Hepatitis Virus

2007 ◽  
Vol 82 (5) ◽  
pp. 2130-2139 ◽  
Author(s):  
Stephen A. Stohlman ◽  
David R. Hinton ◽  
Beatriz Parra ◽  
Roscoe Atkinson ◽  
Cornelia C. Bergmann
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Virus Replication ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Wild Type ◽  
Virus Control ◽  
Ifn Γ

ABSTRACT Replication of the neurotropic mouse hepatitis virus strain JHM (JHMV) is controlled primarily by CD8+ T-cell effectors utilizing gamma interferon (IFN-γ) and perforin-mediated cytotoxicity. CD4+ T cells provide an auxiliary function(s) for CD8+ T-cell survival; however, their direct contribution to control of virus replication and pathology is unclear. To examine a direct role of CD4+ T cells in viral clearance and pathology, pathogenesis was compared in mice deficient in both perforin and IFN-γ that were selectively reconstituted for these functions via transfer of virus-specific memory CD4+ T cells. CD4+ T cells from immunized wild-type, perforin-deficient, and IFN-γ-deficient donors all initially reduced virus replication. However, prolonged viral control by IFN-γ-competent donors suggested that IFN-γ is important for sustained virus control. Local release of IFN-γ was evident by up-regulation of class II molecules on microglia in recipients of IFN-γ producing CD4+ T cells. CD4+ T-cell-mediated antiviral activity correlated with diminished clinical symptoms, pathology, and demyelination. Both wild-type donor CD90.1 and recipient CD90.2 CD4+ T cells trafficked into the central nervous system (CNS) parenchyma and localized to infected white matter, correlating with decreased numbers of virus-infected oligodendrocytes in the CNS. These data support a direct, if limited, antiviral role for CD4+ T cells early during acute JHMV encephalomyelitis. Although the antiviral effector mechanism is initially independent of IFN-γ secretion, sustained control of CNS virus replication by CD4+ T cells requires IFN-γ.

scholarly journals Perforin and Gamma Interferon-Mediated Control of Coronavirus Central Nervous System Infection by CD8 T Cells in the Absence of CD4 T Cells

2004 ◽  
Vol 78 (4) ◽  
pp. 1739-1750 ◽  
Author(s):  
Cornelia C. Bergmann ◽  
Beatriz Parra ◽  
David R. Hinton ◽  
Chandran Ramakrishna ◽  
Konechi C. Dowdell ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Virus Replication ◽  
Cell Types ◽  
Cytolytic Activity ◽  
Gamma Interferon ◽  
Effective Control ◽  
Viral Control ◽  
Ifn Γ

ABSTRACT Infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus produces acute and chronic demyelination. The contributions of perforin-mediated cytolysis and gamma interferon (IFN-γ) secretion by CD8+ T cells to the control of infection and the induction of demyelination were examined by adoptive transfer into infected SCID recipients. Untreated SCID mice exhibited uncontrolled virus replication in all CNS cell types but had little or no demyelination. Memory CD8+ T cells from syngeneic wild-type (wt), perforin-deficient, or IFN-γ-deficient (GKO) donors all trafficked into the infected CNS in the absence of CD4+ T cells and localized to similar areas. Although CD8+ T cells from all three donors suppressed virus replication in the CNS, GKO CD8+ T cells expressed the least antiviral activity. A distinct viral antigen distribution in specific CNS cell types revealed different mechanisms of viral control. While wt CD8+ T cells inhibited virus replication in all CNS cell types, cytolytic activity in the absence of IFN-γ suppressed the infection of astrocytes, but not oligodendroglia. In contrast, cells that secreted IFN-γ but lacked cytolytic activity inhibited replication in oligodendroglia, but not astrocytes. Demyelination was most severe following viral control by wt CD8+ T cells but was independent of macrophage infiltration. These data demonstrate the effective control of virus replication by CD8+ T cells in the absence of CD4+ T cells and support the necessity for the expression of distinct effector mechanisms in the control of viral replication in distinct CNS glial cell types.

scholarly journals CD4 T-Cell-Mediated Demyelination Is Increased in the Absence of Gamma Interferon in Mice Infected with Mouse Hepatitis Virus

2002 ◽  
Vol 76 (14) ◽  
pp. 7329-7333 ◽  
Author(s):  
Lecia Pewe ◽  
Jodie Haring ◽  
Stanley Perlman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Gamma Interferon ◽  
Cd4 T Cell ◽  
Immune Mediated ◽  
Donor Cells ◽  
Ifn Γ

ABSTRACT Mice infected with the murine coronavirus, mouse hepatitis virus, strain JHM (MHV) develop an immune-mediated demyelinating encephalomyelitis. Adoptive transfer of MHV-immune splenocytes depleted of either CD4 or CD8 T cells to infected mice deficient in recombination activation gene 1 resulted in demyelination. We showed previously that the process of CD8 T-cell-mediated demyelination was strongly dependent on the expression of gamma interferon (IFN-γ) by donor cells. In this report, we show, in contrast, that demyelination and lymphocyte infiltration were increased in recipients of IFN-γ−/− CD4 T cells when compared to levels in mice receiving C57BL/6 CD4 T cells.

scholarly journals The Majority of Infiltrating CD8+ T Cells in the Central Nervous System of Susceptible SJL/J Mice Infected with Theiler's Virus Are Virus Specific and Fully Functional

2002 ◽  
Vol 76 (13) ◽  
pp. 6577-6585 ◽  
Author(s):  
Bong-Su Kang ◽  
Michael A. Lyman ◽  
Byung S. Kim
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Demyelinating Disease ◽  
Class I ◽  
Theiler's Virus ◽  
Ctl Response ◽  
The Central Nervous System ◽  
Ifn Γ

ABSTRACT Theiler's virus infection of the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains, such as SJL/J, and serves as a relevant infectious model for human multiple sclerosis. It has been previously suggested that susceptible SJL/J mice do not mount an efficient cytotoxic T-lymphocyte (CTL) response to the virus. In addition, genetic studies have shown that resistance to Theiler's virus-induced demyelinating disease is linked to the H-2D major histocompatibility complex class I locus, suggesting that a compromised CTL response may contribute to the susceptibility of SJL/J mice. Here we show that SJL/J mice do, in fact, generate a CD8+ T-cell response in the CNS that is directed against one dominant (VP3159-166) and two subdominant (VP111-20 and VP3173-181) capsid protein epitopes. These virus-specific CD8+ T cells produce gamma interferon (IFN-γ) and lyse target cells in the presence of the epitope peptides, indicating that these CNS-infiltrating CD8+ T cells are fully functional effector cells. Intracellular IFN-γ staining analysis indicates that greater than 50% of CNS-infiltrating CD8+ T cells are specific for these viral epitopes at 7 days postinfection. Therefore, the susceptibility of SJL/J mice is not due to the lack of an early functional Theiler's murine encephalomyelitis virus-specific CTL response. Interestingly, T-cell responses to all three epitopes are restricted by the H-2Ks molecule, and this skewed class I restriction may be associated with susceptibility to demyelinating disease.

scholarly journals Neuronal Ablation of Alpha/Beta Interferon (IFN-α/β) Signaling Exacerbates Central Nervous System Viral Dissemination and Impairs IFN-γ Responsiveness in Microglia/Macrophages

2020 ◽  
Vol 94 (20) ◽  
Author(s):  
Mihyun Hwang ◽  
Cornelia C. Bergmann
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hepatitis Virus ◽  
Mouse Hepatitis Virus ◽  
Mrna Levels ◽  
Virus Spread ◽  
Beta Interferon ◽  
Ifn Γ ◽  
Alpha Beta ◽  
Β Receptor

ABSTRACT Alpha/beta interferon (IFN-α/β) signaling through the IFN-α/β receptor (IFNAR) is essential to limit virus dissemination throughout the central nervous system (CNS) following many neurotropic virus infections. However, the distinct expression patterns of factors associated with the IFN-α/β pathway in different CNS resident cell populations implicate complex cooperative pathways in IFN-α/β induction and responsiveness. Here we show that mice devoid of IFNAR1 signaling in calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) expressing neurons (CaMKIIcre:IFNARfl/fl mice) infected with a mildly pathogenic neurotropic coronavirus (mouse hepatitis virus A59 strain [MHV-A59]) developed severe encephalomyelitis with hind-limb paralysis and succumbed within 7 days. Increased virus spread in CaMKIIcre:IFNARfl/fl mice compared to IFNARfl/fl mice affected neurons not only in the forebrain but also in the mid-hind brain and spinal cords but excluded the cerebellum. Infection was also increased in glia. The lack of viral control in CaMKIIcre:IFNARfl/fl relative to control mice coincided with sustained Cxcl1 and Ccl2 mRNAs but a decrease in mRNA levels of IFNα/β pathway genes as well as Il6, Tnf, and Il1β between days 4 and 6 postinfection (p.i.). T cell accumulation and IFN-γ production, an essential component of virus control, were not altered. However, IFN-γ responsiveness was impaired in microglia/macrophages irrespective of similar pSTAT1 nuclear translocation as in infected controls. The results reveal how perturbation of IFN-α/β signaling in neurons can worsen disease course and disrupt complex interactions between the IFN-α/β and IFN-γ pathways in achieving optimal antiviral responses. IMPORTANCE IFN-α/β induction limits CNS viral spread by establishing an antiviral state, but also promotes blood brain barrier integrity, adaptive immunity, and activation of microglia/macrophages. However, the extent to which glial or neuronal signaling contributes to these diverse IFN-α/β functions is poorly understood. Using a neurotropic mouse hepatitis virus encephalomyelitis model, this study demonstrated an essential role of IFN-α/β receptor 1 (IFNAR1) specifically in neurons to control virus spread, regulate IFN-γ signaling, and prevent acute mortality. The results support the notion that effective neuronal IFNAR1 signaling compensates for their low basal expression of genes in the IFN-α/β pathway compared to glia. The data further highlight the importance of tightly regulated communication between the IFN-α/β and IFN-γ signaling pathways to optimize antiviral IFN-γ activity.

scholarly journals Kinetics of Virus-Specific CD8+-T-Cell Expansion and Trafficking following Central Nervous System Infection

2003 ◽  
Vol 77 (4) ◽  
pp. 2775-2778 ◽  
Author(s):  
Norman W. Marten ◽  
Stephen A. Stohlman ◽  
Jiehao Zhou ◽  
Cornelia C. Bergmann
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Hepatitis Virus ◽  
Acute Infection ◽  
Central Nervous System Infection ◽  
Cervical Lymph Nodes ◽  
Cognate Antigen ◽  
The Central Nervous System

ABSTRACT CD8+ T cells control acute infection of the central nervous system (CNS) by neurotropic mouse hepatitis virus but do not suffice to achieve sterile immunity. To determine the lag between T-cell priming and optimal activity within the CNS, the accumulation of virus-specific CD8+ T cells in the CNS relative to that in peripheral lymphoid organs was assessed by using gamma interferon-specific ELISPOT assays and class I tetramer staining. Virus-specific CD8+ T cells were first detected in the cervical lymph nodes. Expansion in the spleen was delayed and less pronounced but also preceded accumulation in the CNS. The data further suggest peripheral acquisition of cytolytic function, thus enhancing CD8+-T-cell effector function upon cognate antigen recognition in the CNS.

scholarly journals High-Magnitude, Virus-Specific CD4 T-Cell Response in the Central Nervous System of Coronavirus-Infected Mice

2001 ◽  
Vol 75 (6) ◽  
pp. 3043-3047 ◽  
Author(s):  
Jodie S. Haring ◽  
Lecia L. Pewe ◽  
Stanley Perlman
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Cd4 T Cells ◽  
Hepatitis Virus ◽  
T Cell Response ◽  
Acute Encephalitis ◽  
High Magnitude ◽  
The Central Nervous System ◽  
Ifn Γ

ABSTRACT The neurotropic JHM strain of mouse hepatitis virus (MHV) causes acute encephalitis and chronic demyelinating encephalomyelitis in rodents. Previous results indicated that CD8 T cells infiltrating the central nervous system (CNS) were largely antigen specific in both diseases. Herein we show that by 7 days postinoculation, nearly 30% of the CD4 T cells in the acutely infected CNS were MHV specific by using intracellular gamma interferon (IFN-γ) staining assays. In mice with chronic demyelination, 10 to 15% of the CD4 T cells secreted IFN-γ in response to MHV-specific peptides. Thus, these results show that infection of the CNS is characterized by a large influx of CD4 T cells specific for MHV and that these cells remain functional, as measured by cytokine secretion, in mice with chronic demyelination.

scholarly journals Failure to Suppress the Expansion of the Activated Cd4 T Cell Population in Interferon γ–Deficient Mice Leads to Exacerbation of Experimental Autoimmune Encephalomyelitis

2000 ◽  
Vol 192 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Cong-Qiu Chu ◽  
Susan Wittmer ◽  
Dyana K. Dalton
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Cd4 T Cells ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Ifn Γ ◽  
Experimental Autoimmune

Mice deficient in interferon (IFN)-γ or IFN-γ receptor develop progressive and fatal experimental autoimmune encephalomyelitis (EAE). We demonstrate that CD4 T cells lacking IFN-γ production were required to passively transfer EAE, indicating that they were disease-mediating cells in IFN-γ knockout (KO) mice. IFN-γ KO mice accumulated 10–16-fold more activated CD4 T cells (CD4+CD44hi) than wild-type mice in the central nervous system during EAE. CD4+CD44hi T cells in the spleen and central nervous system of IFN-γ KO mice during EAE showed markedly increased in vivo proliferation and significantly decreased ex vivo apoptosis compared with those of wild-type mice. IFN-γ KO CD4+CD44hi T cells proliferated extensively to antigen restimulation in vitro and accumulated larger numbers of live CD4+ CD44hi T cells. IFN-γ completely suppressed proliferation and significantly induced apoptosis of CD4+CD44hi T cells responding to antigen and hence inhibited accumulation of live, activated CD4 T cells. We thus present novel in vivo and in vitro evidence that IFN-γ may limit the extent of EAE by suppressing expansion of activated CD4 T cells.

scholarly journals IFN-γ– and IL-10–expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis

2011 ◽  
Vol 208 (8) ◽  
pp. 1571-1577 ◽  
Author(s):  
Jingxian Zhao ◽  
Jincun Zhao ◽  
Craig Fett ◽  
Kathryn Trandem ◽  
Erica Fleming ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cytokine Production ◽  
Intracellular Cytokine Staining ◽  
Virus Antigen ◽  
T Cell Epitopes ◽  
Ifn Γ

Foxp3+ CD4 regulatory T cells (T reg cells) are important in limiting immunopathology in infections. However, identifying pathogen-specific epitopes targeted by these cells has been elusive. Using MHC class II/peptide tetramers and intracellular cytokine staining, we identify T reg cells recognizing two virus-specific CD4 T cell epitopes in the coronavirus-infected central nervous system as well as naive T cell precursor pools. These T reg cells are detected at the same time as effector T cells (T eff cells) exhibiting the same specificity and can suppress T eff cell proliferation after stimulation with cognate peptide. These virus-specific T reg cells may be especially effective in inhibiting the immune response during the peak of infection, when virus antigen is maximal. Furthermore, these T reg cells express both IL-10 and IFN-γ after peptide stimulation. IFN-γ expression is maintained during both acute and chronic phases of infection. Identification of T reg cell target epitopes by cytokine production is also applicable in autoimmune disease because myelin oligodendrocyte glycoprotein–specific Foxp3+ T reg cells express IL-10 and IL-17 at the peak of disease in mice with experimental autoimmune encephalomyelitis. These results show that pathogen epitope-specific Foxp3+ T reg cells can be identified on the basis of cytokine production.

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