CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity

Reddehase, Matthias J.; Mutter, Wolfgang; Münch, Konrad; Bühring, Hans‐Jörg; Koszinowski, Ulrich H.

doi:10.1128/jvi.61.10.3102-3108.1987

Cited by 390 publications

(159 citation statements)

References 37 publications

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“…Infection spreads to astrocytes within the brain parenchyma only in the absence of an effective CD8 + T cell response [10]. Reports by other groups have also established the importance of CD8 + T cells for control of primary infection [11,12]. Likewise, previous studies from our laboratory have shown that antigen-specific CD8 + T cells persist within the brain even in the absence of detectable viral protein [13].…”

Section: Introductionmentioning

confidence: 56%

“…Cells of the B-lineage enter the CNS in response to acute viral infection, and like T cells, they are retained within the brain into the chronic phase. Although CD8 + T cells play a critical role in controlling viral spread during acute brain infection [10,11], prolonged immune responses within the brain following MCMV infection are characterized by persistence of Abproducing B cells, chronic microglial cell activation, and retention of virus-specific memory CD8 + T cells [7,13]. Like other herpesviruses, MCMV establishes latency after control of acute infection and clearance of detectable viral antigen.…”

Section: Introductionmentioning

confidence: 99%

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Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Lokensgard

Mutnal

Prasad

et al. 2016

J Neuroinflammation

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BackgroundChemokines produced by reactive glia drive migration of immune cells and previous studies from our laboratory have demonstrated that CD19+ B cells infiltrate the brain. In this study, in vivo and in vitro experiments investigated the role of reactive glial cells in recruitment and survival of B-lineage cells in response to (murine cytomegalovirus) MCMV infection.MethodsFlow cytometric analysis was used to assess chemokine receptor expression on brain-infiltrating B cells. Real-time RT-PCR and ELISA were used to measure chemokine levels. Dual-immunohistochemical staining was used to co-localize chemokine production by reactive glia. Primary glial cell cultures and migration assays were used to examine chemokine-mediated recruitment. Astrocyte: B cell co-cultures were used to investigate survival and proliferation.ResultsThe chemokine receptors CXCR3, CXCR5, CCR5, and CCR7 were detected on CD19+ cells isolated from the brain during MCMV infection. In particular, CXCR3 was found to be elevated on an increasing number of cells over the time course of infection, and it was the primary chemokine receptor expressed at 60 days post infection Quite different expression kinetics were observed for CXCR5, CCR5, and CCR7, which were elevated on the highest number of cells early during infection and decreased by 14, 30, and 60 days post infection Correspondingly, elevated levels of CXCL9, CXCL10, and CXCL13, as well as CCL5, were found within the brains of infected animals, and only low levels of CCL3 and CCL19 were detected. Differential expression of CXCL9/CXCL10 and CXCL13 between microglia and astrocytes was apparent, and B cells moved towards supernatants from MCMV-infected microglia, but not astrocytes. Pretreatment with neutralizing Abs to CXCL9 and CXCL10 inhibited this migration. In contrast, neutralizing Abs to the ligand of CXCR5 (i.e., CXCL13) did not significantly block chemotaxis. Proliferation of brain-infiltrating B cells was detected at 7 days post infection and persisted through the latest time tested (60 days post infection). Finally, astrocytes produce BAFF (B cell activating factor of the TNF family) and promote proliferation of B cells via cell-to-cell contact.ConclusionsCXCR3 is the primary chemokine receptor on CD19+ B cells persisting within the brain, and migration to microglial cell supernatants is mediated through this receptor. Correspondingly, microglial cells produce CXCL9 and CXCL10, but not CXCL13. Reactive astrocytes promote B cell proliferation.

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Section: Introductionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Lokensgard

Mutnal

Prasad

et al. 2016

J Neuroinflammation

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“…Prolonged immune responses within the brain following MCMV infection are characterized by persistence of antibody-producing B-cells, chronic microglial cell activation, and retention of MCMV-specific effector-memory CD8 1 T-cells (Mutnal et al, 2011b;Mutnal et al, 2012). Although CD8 1 T-cells play an important role in controlling acute brain infection (Reddehase et al, 1987(Reddehase et al, , 1985, the chronic presence of these IFN-g-producing T-cells may be damaging to the brain. Although retention of antigen-specific CD8 1 T-cells following MCMV infection helps to protect against virus reactivation, they are also responsible for long-term activation of microglia throughout the brain (Mutnal et al, 2011b).…”

Section: Introductionmentioning

confidence: 99%

Glial cells suppress postencephalitic CD8⁺ T lymphocytes through PD‐L1

Schachtele

Sheng

et al. 2014

Glia

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Engagement of the programmed death (PD)-1 receptor on activated cells by its ligand (PD-L1) is a mechanism for suppression of activated T-lymphocytes. Microglia, the resident inflammatory cells of the brain, are important for pathogen detection and initiation of innate immunity, however, a novel role for these cells as immune regulators has also emerged. PD-L1 on microglia has been shown to negatively regulate T-cell activation in models of multiple sclerosis and acute viral encephalitis. In this study, we investigated the role of glial cell PD-L1 in controlling encephalitogenic CD8+ T-lymphocytes, which infiltrate the brain to manage viral infection, but remain to produce chronic neuroinflammation. Using a model of chronic neuroinflammation following murine cytomegalovirus (MCMV)-induced encephalitis, we found that CD8+ T-cells persisting within the brain expressed PD-1. Conversely, activated microglia expressed PD-L1. In vitro, primary murine microglia, which express low basal levels of PD-L1, upregulated the co-inhibitory ligand upon IFN-γ-treatment. Blockade of the PD-1: PD-L1 pathway in microglial: CD8+ T-cell co-cultures increased T-cell IFN-γ and interleukin (IL)-2 production. We observed a similar phenomenon following blockade of this co-inhibitory pathway in astrocyte: CD8+ T-cell co-cultures. Using ex vivo cultures of brain leukocytes, including microglia and CD8+ T-cells, obtained from mice with MCMV-induced chronic neuroinflammation, we found that neutralization of either PD-1 or PD-L1 increased IFN-γ production from virus-specific CD8+ T-cells stimulated with MCMV IE1168-176 peptide. These data demonstrate that microglia and astrocytes control antiviral T-cell responses and suggest a therapeutic potential of PD1: PD-L1 modulation to manage the deleterious consequences of uncontrolled neuroinflammation.

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“…Recognition of nonstructural viral proteins by the human immune system that raise an effective immune response and mediate protective immunity has been reported in several viral systems (39,40). We describe for the first time PBMC that specifically recognize HBxAg, a nonstructural protein of HBV.…”

Section: Discussionmentioning

confidence: 92%

Immune response of peripheral blood mononuclear cells to HBx-antigen of hepatitis B virus

et al. 1991

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The hepatitis B virus genome encodes a transcriptional transactivator protein designated HBxAg. We have investigated whether this antigen is a target structure for human T-lymphocytes. Using recombinant HBxAg protein, we found HBxAg-specific stimulation of peripheral blood mononuclear cells in patients with acute hepatitis B virus infection (6 of 6) and chronic hepatitis B virus infection (6 of 17) but not in healthy individuals. With HBxAg-specific synthetic polypeptides, several T-cell epitopes were identified. Most were located in the carboxyterminal half of the HBxAg protein. Five T-cell clones specific for a T-cell epitope located at the carboxyterminal region of HBxAg were established and found to belong to the CD2/CD4-positive, CD8-negative subtype. These data establish for the first time HBxAg as an antigen in the cellular immune response.

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CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity

Cited by 390 publications

References 37 publications

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Glial cells suppress postencephalitic CD8⁺ T lymphocytes through PD‐L1

Immune response of peripheral blood mononuclear cells to HBx-antigen of hepatitis B virus

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CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity

Cited by 390 publications

References 37 publications

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Glial cells suppress postencephalitic CD8+ T lymphocytes through PD‐L1

Immune response of peripheral blood mononuclear cells to HBx-antigen of hepatitis B virus

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Glial cells suppress postencephalitic CD8⁺ T lymphocytes through PD‐L1