Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure.

Odermatt, Bernhard; Eppler, M; Leist, Thomas; Hengartner, Hans; Zinkernagel, Rolf M.

doi:10.1073/pnas.88.18.8252

Cited by 216 publications

(152 citation statements)

References 54 publications

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“…Interestingly, a good relationship between serum anti-HBs and Tim-3 expression on CD8 + T was found in our HBV model mice ( Figure 5 increase in titer when CD8 + T cell function is impaired or absent (25)(26)(27)(28). This competitive coexistence may be beneficial to the host by averting a combination of strong cytotoxicity and antibody responses that may favor immunopathology (31,32). Recent study has shown that Tim-3 upregulation in HIV infection might be the result of a physiological response to chronic immune activation necessary to hold CD8 + T cell-dependent immunopathology in check (13), indicating that Tim-3 might indirectly affect neutralizing antibody production by regulating CD8 + T cell function.…”

Section: Discussionmentioning

confidence: 66%

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

Hou

Zhang

et al. 2009

Cell Mol Immunol

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Section: Discussionmentioning

confidence: 66%

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

Hou

Zhang

et al. 2009

Cell Mol Immunol

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“…3 D and E). This corresponded with the reduced disruption of the lymphoid architecture and increased cellularity observed during chronic LCMV infection in mice depleted of CD8 ϩ T cells (data not shown) (9). Mice deficient in perforin and IFN-␥ showed improved tracer accumulation in the WP after CL-13 infection when compared with WT mice (SI Fig.…”

Section: Resultsmentioning

confidence: 88%

“…Chronic LCMV infection results in reduced cellularity and altered splenic architecture (9). Enhanced infection of dendritic cells (DC), resulting in reduced T cell stimulatory capacity and destruction of the DC, has been proposed as one mechanism by which CL-13 initiates immunosuppression within the host (8,10).…”

mentioning

confidence: 99%

Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection

Mueller

Matloubian

Clemens

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

212

239

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Many chronic viral infections are marked by pathogen persistence and a generalized immunosuppression. The exact mechanisms by which this occurs are still unknown. Using a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, we demonstrate viral targeting of fibroblastic reticular cells (FRC) in the lymphoid organs. The FRC stromal networks are critical for proper lymphoid architecture and function. High numbers of FRC were infected by LCMV clone 13, which causes a chronic infection, whereas few were infected by the acute strain, LCMV Armstrong. The function of the FRC conduit network was altered after clone 13 infection by the action of CD8 ؉ T cells. Importantly, expression of the inhibitory programmed death ligand 1, which was up-regulated on FRC after infection, reduced early CD8 ؉ T cell-mediated immunopathology and prevented destruction of the FRC architecture in the spleen. Together, this reveals an important tropism during a persistent viral infection. These data also suggest that the inhibitory PD-1 pathway, which likely evolved to prevent excessive immunopathology, may contribute to viral persistence in FRC during chronic infection.immunopathology ͉ stromal cells ͉ viral infection M any acute and chronic viral infections induce a generalized immunosuppression (1, 2). This suppression of immunity is often transient, occurring during the acute phase of infection; however, prolonged suppression can also occur during certain chronic viral infections. The mechanisms of virus-induced immunosuppression are complex and varied (1-3). Infection of mice with lymphocytic choriomeningitis virus (LCMV) is a useful model to dissect the mechanisms of viral persistence and immunosuppression. The clone 13 (CL-13) strain of LCMV results in a chronic infection in adult mice, marked by persisting virus and a generalized immunosuppression. Viral load rises rapidly within days and remains high over a prolonged period, suppressing specific immunity by inducing an hierarchical loss of CD8 ϩ T cell function (4, 5). This CL-13 chronic infection is also associated with increased susceptibility to opportunistic secondary infections (6-8).Chronic LCMV infection results in reduced cellularity and altered splenic architecture (9). Enhanced infection of dendritic cells (DC), resulting in reduced T cell stimulatory capacity and destruction of the DC, has been proposed as one mechanism by which CL-13 initiates immunosuppression within the host (8, 10). Although DC in the spleen can be infected by LCMV CL-13, this represents a relatively small proportion of total infected cells. It follows that other cell types are infected by CL-13 and likely contribute to the pronounced immunosuppression and architectural disruption of lymphoid organs that are observed after infection.Through a detailed kinetic examination of the cell types infected during LCMV CL-13 infection we discovered that fibroblastic reticular cells (FRC) are an important target of infection by this virus. Secondary lymphoid tissues are supported by a c...

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“…That decrease appeared less profound than the one we describe here, probably reflecting different mechanisms of DC elimination during CD4 ϩ T cell responses compared with CD8 ϩ T cell responses. DC elimination has also been demonstrated by histological means in mice exposed to viruses that induce strong CTL immune responses (29).…”

Section: Discussionmentioning

confidence: 99%

CD8+ T Cell-Dependent Elimination of Dendritic Cells In Vivo Limits the Induction of Antitumor Immunity

Hermans

Ritchie

Yang

et al. 2000

The Journal of Immunology

211

206

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The fate of dendritic cells (DC) after they have initiated a T cell immune response is still undefined. We have monitored the migration of DC labeled with a fluorescent tracer and injected s.c. into naive mice or into mice with an ongoing immune response. DC not loaded with Ag were detected in the draining lymph node in excess of 7 days after injection with maximum numbers detectable ∼40 h after transfer. In contrast, DC that had been loaded with an MHC class I-binding peptide disappeared from the lymph node with kinetics that parallel the known kinetics of activation of CD8+ T cells to effector function. In the presence of high numbers of specific CTL precursors, as in TCR transgenic mice, DC numbers were significantly decreased by 72 h after injection. The rate of DC disappearance was extremely rapid and efficient in recently immunized mice and was slower in “memory” mice in which memory CD8+ cells needed to reacquire effector function before mediating DC elimination. We also show that CTL-mediated clearance of Ag-loaded DC has a notable effect on immune responses in vivo. Ag-specific CD8+ T cells failed to divide in response to Ag presented on a DC if the DC were targets of a pre-existing CTL response. The induction of antitumor immunity by tumor Ag-loaded DC was also impaired. Therefore, CTL-mediated clearance of Ag-loaded DC may serve as a negative feedback mechanism to limit the activity of DC within the lymph node.

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Virus-triggered acquired immunodeficiency by cytotoxic T-cell-dependent destruction of antigen-presenting cells and lymph follicle structure.

Cited by 216 publications

References 54 publications

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection

CD8+ T Cell-Dependent Elimination of Dendritic Cells In Vivo Limits the Induction of Antitumor Immunity

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