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Departments of
*
Neurology,
Molecular Microbiology and Immunology, and
Pathology, University of Southern California School of Medicine, Los Angeles, CA 90033; and
§
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322
Mice infected with the neurotropic JHM strain of mouse hepatitis
virus (JHMV) clear infectious virus; nevertheless, virus persists in
the CNS as noninfectious RNA, resulting in ongoing primary
demyelination. Phenotypic and functional analysis of CNS infiltrating
cells during acute infection revealed a potent regional
CD8+ T cell response comprising up to 50% virus-specific T
cells. The high prevalence of virus-specific T cells correlated with ex
vivo cytolytic activity and efficient reduction in viral titers.
Progressive viral clearance coincided with the loss of cytolytic
activity, but retention of IFN-
secretion and increased expression
of the early activation marker CD69, indicating differential regulation
of effector function. Although the total number of infiltrating T cells
declined following clearance of infectious virus, CD8+ T
cells, both specific for the dominant viral epitopes and of unknown
specificity, were retained within the CNS, suggesting an ongoing T cell
response during persistent CNS infection involving a virus-independent
component. Reversed immunodominance within the virus-specific
CD8+ T cell population further indicated epitope-specific
regulation, supporting ongoing T cell activation. Even in the absence
of infectious virus, the CNS thus provides an environment that
maintains both unspecific and Ag-specific CD8+ T cells with
restricted effector function. Chronic T cell stimulation may thus play
a role in preventing viral recrudescence, while increasing the risk of
pathological conditions, such as demyelination.
This article has been cited by other articles:
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K. C. MacNamara, M. M. Chua, J. J. Phillips, and S. R. Weiss Contributions of the Viral Genetic Background and a Single Amino Acid Substitution in an Immunodominant CD8+ T-Cell Epitope to Murine Coronavirus Neurovirulence J. Virol., July 15, 2005; 79(14): 9108 - 9118. [Abstract] [Full Text] [PDF]
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K. C. MacNamara, M. M. Chua, P. T. Nelson, H. Shen, and S. R. Weiss Increased Epitope-Specific CD8+ T Cells Prevent Murine Coronavirus Spread to the Spinal Cord and Subsequent Demyelination J. Virol., March 15, 2005; 79(6): 3370 - 3381. [Abstract] [Full Text] [PDF]
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Y. V. Mendez-Fernandez, M. J. Hansen, M. Rodriguez, and L. R. Pease Anatomical and Cellular Requirements for the Activation and Migration of Virus-Specific CD8+ T Cells to the Brain during Theiler's Virus Infection J. Virol., March 1, 2005; 79(5): 3063 - 3070. [Abstract] [Full Text] [PDF]
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C. Ramakrishna, S. A. Stohlman, R. A. Atkinson, D. R. Hinton, and C. C. Bergmann Differential Regulation of Primary and Secondary CD8+ T Cells in the Central Nervous System J. Immunol., November 15, 2004; 173(10): 6265 - 6273. [Abstract] [Full Text] [PDF]
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E. J. Wherry and R. Ahmed Memory CD8 T-Cell Differentiation during Viral Infection J. Virol., June 1, 2004; 78(11): 5535 - 5545. [Full Text] [PDF]
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J. A. Deane, M. J. Trifilo, C. M. Yballe, S. Choi, T. E. Lane, and D. A. Fruman Enhanced T Cell Proliferation in Mice Lacking the p85{beta} Subunit of Phosphoinositide 3-Kinase J. Immunol., June 1, 2004; 172(11): 6615 - 6625. [Abstract] [Full Text] [PDF]
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C. C. Bergmann, B. Parra, D. R. Hinton, C. Ramakrishna, K. C. Dowdell, and S. A. Stohlman Perforin and Gamma Interferon-Mediated Control of Coronavirus Central Nervous System Infection by CD8 T Cells in the Absence of CD4 T Cells J. Virol., February 15, 2004; 78(4): 1739 - 1750. [Abstract] [Full Text] [PDF]
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A. A. Dandekar, D. Anghelina, and S. Perlman Bystander CD8 T-Cell-Mediated Demyelination is Interferon-{gamma}-Dependent in a Coronavirus Model of Multiple Sclerosis Am. J. Pathol., February 1, 2004; 164(2): 363 - 369. [Abstract] [Full Text] [PDF]
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D. D. Sloan, G. Zahariadis, C. M. Posavad, N. T. Pate, S. J. Kussick, and K. R. Jerome CTL Are Inactivated by Herpes Simplex Virus-Infected Cells Expressing a Viral Protein Kinase J. Immunol., December 15, 2003; 171(12): 6733 - 6741. [Abstract] [Full Text] [PDF]
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M. Moniuszko, C. Brown, R. Pal, E. Tryniszewska, W.-P. Tsai, V. M. Hirsch, and G. Franchini High Frequency of Virus-Specific CD8+ T Cells in the Central Nervous System of Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251 J. Virol., November 15, 2003; 77(22): 12346 - 12351. [Abstract] [Full Text] [PDF]
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T. S. Kim and S. Perlman Protection Against CTL Escape and Clinical Disease in a Murine Model of Virus Persistence J. Immunol., August 15, 2003; 171(4): 2006 - 2013. [Abstract] [Full Text] [PDF]
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C. Ramakrishna, C. C. Bergmann, R. Atkinson, and S. A. Stohlman Control of Central Nervous System Viral Persistence by Neutralizing Antibody J. Virol., April 15, 2003; 77(8): 4670 - 4678. [Abstract] [Full Text] [PDF]
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E. J. Wherry, J. N. Blattman, K. Murali-Krishna, R. van der Most, and R. Ahmed Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment J. Virol., April 15, 2003; 77(8): 4911 - 4927. [Abstract] [Full Text] [PDF]
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M. J. Trifilo, C. C. Bergmann, W. A. Kuziel, and T. E. Lane CC Chemokine Ligand 3 (CCL3) Regulates CD8+-T-Cell Effector Function and Migration following Viral Infection J. Virol., April 1, 2003; 77(7): 4004 - 4014. [Abstract] [Full Text] [PDF]
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C. C. Bergmann, B. Parra, D. R. Hinton, R. Chandran, M. Morrison, and S. A. Stohlman Perforin-Mediated Effector Function Within the Central Nervous System Requires IFN-{gamma}-Mediated MHC Up-Regulation J. Immunol., March 15, 2003; 170(6): 3204 - 3213. [Abstract] [Full Text] [PDF]
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J. Zhou, S. A. Stohlman, D. R. Hinton, and N. W. Marten Neutrophils Promote Mononuclear Cell Infiltration During Viral-Induced Encephalitis J. Immunol., March 15, 2003; 170(6): 3331 - 3336. [Abstract] [Full Text] [PDF]
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N. W. Marten, S. A. Stohlman, J. Zhou, and C. C. Bergmann Kinetics of Virus-Specific CD8+-T-Cell Expansion and Trafficking following Central Nervous System Infection J. Virol., February 15, 2003; 77(4): 2775 - 2778. [Abstract] [Full Text] [PDF]
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 R. G. v. d. Most, K. Murali-Krishna, and R. Ahmed Prolonged presence of effector-memory CD8 T cells in the central nervous system after dengue virus encephalitis Int. Immunol., January 1, 2003; 15(1): 119 - 125. [Abstract] [Full Text] [PDF]
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A. Yu, J. Zhou, N. Marten, C. C. Bergmann, M. Mammolenti, R. B. Levy, and T. R. Malek Efficient Induction of Primary and Secondary T Cell-Dependent Immune Responses In Vivo in the Absence of Functional IL-2 and IL-15 Receptors J. Immunol., January 1, 2003; 170(1): 236 - 242. [Abstract] [Full Text] [PDF]
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A. A. Dandekar and S. Perlman Virus-Induced Demyelination in Nude Mice Is Mediated by {gamma}{delta} T Cells Am. J. Pathol., October 1, 2002; 161(4): 1255 - 1263. [Abstract] [Full Text] [PDF]
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J. Zhou, S. A. Stohlman, R. Atkinson, D. R. Hinton, and N. W. Marten Matrix Metalloproteinase Expression Correlates with Virulence following Neurotropic Mouse Hepatitis Virus Infection J. Virol., June 27, 2002; 76(15): 7374 - 7384. [Abstract] [Full Text] [PDF]
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S.-I. Tschen, C. C. Bergmann, C. Ramakrishna, S. Morales, R. Atkinson, and S. A. Stohlman Recruitment Kinetics and Composition of Antibody-Secreting Cells Within the Central Nervous System Following Viral Encephalomyelitis J. Immunol., March 15, 2002; 168(6): 2922 - 2929. [Abstract] [Full Text] [PDF]
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C. Ramakrishna, S. A. Stohlman, R. D. Atkinson, M. J. Shlomchik, and C. C. Bergmann Mechanisms of Central Nervous System Viral Persistence: the Critical Role of Antibody and B Cells J. Immunol., February 1, 2002; 168(3): 1204 - 1211. [Abstract] [Full Text] [PDF]
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T. Liu, K. M. Khanna, B. N. Carriere, and R. L. Hendricks Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons J. Virol., November 15, 2001; 75(22): 11178 - 11184. [Abstract] [Full Text] [PDF]
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A. E. Matthews, S. R. Weiss, M. J. Shlomchik, L. G. Hannum, J. L. Gombold, and Y. Paterson Antibody Is Required for Clearance of Infectious Murine Hepatitis Virus A59 from the Central Nervous System, But Not the Liver J. Immunol., November 1, 2001; 167(9): 5254 - 5263. [Abstract] [Full Text] [PDF]
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M. T. Liu, H. S. Keirstead, and T. E. Lane Neutralization of the Chemokine CXCL10 Reduces Inflammatory Cell Invasion and Demyelination and Improves Neurological Function in a Viral Model of Multiple Sclerosis J. Immunol., October 1, 2001; 167(7): 4091 - 4097. [Abstract] [Full Text] [PDF]
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C. C. Bergmann, C. Ramakrishna, M. Kornacki, and S. A. Stohlman Impaired T Cell Immunity in B Cell-Deficient Mice Following Viral Central Nervous System Infection J. Immunol., August 1, 2001; 167(3): 1575 - 1583. [Abstract] [Full Text] [PDF]
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R. Holtappels, J. Podlech, N. K. A. Grzimek, D. Thomas, M.-F. Pahl-Seibert, and M. J. Reddehase Experimental Preemptive Immunotherapy of Murine Cytomegalovirus Disease with CD8 T-Cell Lines Specific for ppM83 and pM84, the Two Homologs of Human Cytomegalovirus Tegument Protein ppUL83 (pp65) J. Virol., July 15, 2001; 75(14): 6584 - 6600. [Abstract] [Full Text]
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J. S. Haring, L. L. Pewe, and S. Perlman High-Magnitude, Virus-Specific CD4 T-Cell Response in the Central Nervous System of Coronavirus-Infected Mice J. Virol., March 15, 2001; 75(6): 3043 - 3047. [Abstract] [Full Text]
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P. R. Walker, T. Calzascia, V. Schnuriger, N. Scamuffa, P. Saas, N. de Tribolet, and P.-Y. Dietrich The Brain Parenchyma Is Permissive for Full Antitumor CTL Effector Function, Even in the Absence of CD4 T Cells J. Immunol., September 15, 2000; 165(6): 3128 - 3135. [Abstract] [Full Text] [PDF]
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N. W. Marten, S. A. Stohlman, and C. C. Bergmann Role of Viral Persistence in Retaining CD8+ T Cells within the Central Nervous System J. Virol., September 1, 2000; 74(17): 7903 - 7910. [Abstract] [Full Text]
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G. F. Wu, A. A. Dandekar, L. Pewe, and S. Perlman CD4 and CD8 T Cells Have Redundant But Not Identical Roles in Virus-Induced Demyelination J. Immunol., August 15, 2000; 165(4): 2278 - 2286. [Abstract] [Full Text] [PDF]
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 B. Rehermann Intrahepatic T Cells in Hepatitis B: Viral Control versus Liver Cell Injury J. Exp. Med., April 17, 2000; 191(8): 1263 - 1268. [Full Text] [PDF]
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B. Parra, M. T. Lin, S. A. Stohlman, C. C. Bergmann, R. Atkinson, and D. R. Hinton Contributions of Fas-Fas Ligand Interactions to the Pathogenesis of Mouse Hepatitis Virus in the Central Nervous System J. Virol., March 1, 2000; 74(5): 2447 - 2450. [Abstract] [Full Text]
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