Strain-Dependent Requirement for IFN-γ for Respiratory Control and Immunotherapy in Murine Gammaherpesvirus Infection

Tsai, Chin‐Feng; Hu, Zhuting; Zhang, Weijun; Usherwood, Edward J.

doi:10.1089/vim.2011.0004

Cited by 17 publications

(20 citation statements)

References 40 publications

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“…Our previous work showed that CD4, but not CD8, T cells were critical for the regression of S11 B lymphoma cells latently infected with MHV-68 in BALB/c mice (15). The present study was performed with the C57BL/6 mouse strain, which may partly explain the different findings, given the demonstrated strain dependence of MHV-68-specific T cell responses (5,8). The two cell lines were also generated in different ways, SL1 cell through direct infection of fetal liver-derived B cells, whereas the S11 cell line was cultured from a lymphoma that developed in a long-term-infected mouse.…”

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confidence: 67%

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CD4 and CD8 T Cells Directly Recognize Murine Gammaherpesvirus 68-Immortalized Cells and Prevent Tumor Outgrowth

Liang

Crepeau

Zhang

et al. 2013

J Virol

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There has been extensive research regarding T cell recognition of Epstein-Barr virus-transformed cells; however, less is known regarding the recognition of B cells immortalized by gamma-2 herpesviruses. Here we show that B cells immortalized by murine gammaherpesvirus 68 (MHV-68, ␥HV-68) can be controlled by either CD4 or CD8 T cells in vivo. We present evidence for the direct recognition of infected B cells by CD4 and CD8 T cells. These data will help in the development of immunotherapeutic approaches combating gamma-2 herpesvirus-related disease.T cell immunity is critical to control virus replication and latently infected cells in most herpesvirus infections. Using the murine gammaherpesvirus 68 (MHV-68, ␥HV-68) mouse model of gamma-2 herpesvirus infection, we now have a good understanding of the immunological factors necessary to control virus replication (1-9). However, we have a much poorer understanding of T cell recognition of latently infected B cells. This has been due largely to our inability to immortalize B cells by MHV-68 infection in vitro. However, our recently published work describes a methodology by which immature B cells can be immortalized by MHV-68 (10). These cells grow as tumors in immunodeficient mice but not immunocompetent mice, indicating immunological control of the outgrowth of MHV-68-infected B cells (10). To determine the key cell types responsible for this protection, we used an adoptive transfer system. We transferred purified T lymphocytes, B lymphocytes, or both T and B lymphocytes from naïve mice into RAG2 Ϫ/Ϫ mice. MHV-68-immortalized SL1 cells were then injected into the mice, and tumor growth was monitored. In mice receiving no T cells or only B cells, the tumor grew to a size necessitating euthanasia by approximately 30 to 40 days postinjection (Fig. 1A). However, mice receiving either T cells alone or T and B cells survived for Ͼ150 days postinjection with no tumor growth (Fig. 1B). These data indicated that T cells were the predominant cells responsible for mediating protection against the outgrowth of MHV-68-immortalized tumor cells. Importantly, we did not observe virus reactivation from SL1 cells after injection in vivo, as no viral spread to the host was detectable, measured by PCR for the viral genome in the spleens of wild-type or RAG2 Ϫ/Ϫ mutant mice injected with SL1 cells (data not shown).Next, we adoptively transferred purified CD8 or CD4 T cells into RAG2Ϫ/Ϫ mutant mice, injected them with SL1 cells, and 001). (C) RAG2Ϫ/Ϫ mutant mice received SL1 cells and T cells (Pan T), CD4 T cells, CD8 T cells, or a PBS control. Cells were isolated by negative selection by magnetic cell separation. The control group received PBS buffer only (n ϭ 10; log-rank test; ***, P Ͻ 0.001).

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confidence: 67%

“…Using the murine gammaherpesvirus 68 (MHV-68, ␥HV-68) mouse model of gamma-2 herpesvirus infection, we now have a good understanding of the immunological factors necessary to control virus replication (1)(2)(3)(4)(5)(6)(7)(8)(9). However, we have a much poorer understanding of T cell recognition of latently infected B cells.…”

mentioning

confidence: 99%

CD4 and CD8 T Cells Directly Recognize Murine Gammaherpesvirus 68-Immortalized Cells and Prevent Tumor Outgrowth

Liang

Crepeau

Zhang

et al. 2013

J Virol

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“…CD4 T cells in IRF-1 Ϫ/Ϫ mice are thought to be skewed toward a Th2 phenotype, with decreased expression of IFN-␥ due to attenuated interleukin-12 (IL-12) expression (27). IFN-␥ is induced during the late stages of acute MHV68 infection (28) and facilitates clearance of lytically replicating MHV68 in the lungs (29). Given the importance of IFN-␥ in MHV68 clearance, serum IFN-␥ levels were measured at 9 days postinfection.…”

Section: Resultsmentioning

confidence: 99%

Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection

Mboko

Rekow

Ledwith

et al. 2017

J Virol

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Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in Ͼ95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection.IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I interferon (IFN) signaling and interferon regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.KEYWORDS IRF-1, acute infection, gammaherpesvirus, interferon, viral replication G ammaherpesviruses are ubiquitous pathogens that establish lifelong infection in a majority of the adult population and are associated with cancer (1-3). Similar to replication of other viruses, replication of both human (Epstein-Barr virus [EBV] and Kaposi's sarcoma-associated herpesvirus [KSHV]) and murine (mouse gammaherpesvirus 68[MHV68]) gammaherpesviruses is suppressed by type I and type II interferons (IFNs), two partially overlapping yet distinct host networks that are critical for the control of gammaherpesvirus infection (4-10). In the case of MHV68, both acute and chronic MHV68 infection is attenuated by type I and type II IFNs (4,6,11,12). While the antiviral role of IFNs in the context of gammaherpesvirus infection, including in vivo, is firmly established, the mechanism by which this restriction is imposed and the molecular players involved in this response are still being defined.Interferon regulatory factor 1 (IRF-1) is a broadly antiviral transcription factor that restricts replication of diverse RNA and DNA viruses in cell culture via a poorly understood mechanism (13, 14). While initially IRF-1 was thought to induce type I interferon (IFN) expression (15)

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“…1B). Interestingly, IFNγ does protect against lethal infection with murine cytomegalovirus (Pomeroy et al , 1998), dengue virus (Fagundes et al , 2011; Costa et al , 2012) and murine gamma-herpesvirus (Lee et al , 2009; Tsai et al , 2011). In contrast, IFNγ signaling has no discernible impact on survival in response to vesicular stomatitis virus, Semliki forest virus, or influenza virus [Huang et al , 1993; Muller et al , 1994; van den Broek et al , 1995].…”

Section: Resultsmentioning

confidence: 99%

Sustained inflammation and differential expression of interferons type I and III in PVM-infected interferon-gamma (IFN γ ) gene-deleted mice

et al. 2014

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Interferon gamma (IFNγ) has complex immunomodulatory and antiviral properties. While IFNγ is detected in the airways in response to infection with the pneumovirus pathogen, pneumonia virus of mice (PVM; Family Paramyxoviridae), its role in promoting disease has not been fully explored. Here, we evaluate PVM infection in IFNγ−/− mice. Although the IFNγ gene-deletion has no impact on weight loss, survival or virus kinetics, expression of IFNβ, IFNλ2/3 and IFN-stimulated 2'–5' oligoadenylate synthetases was significantly diminished compared to wild-type counterparts. Furthermore, PVM infection in IFNγ−/− mice promoted prominent inflammation, including eosinophil and neutrophil infiltration into the airways and lung parenchyma, observed several days after peak virus titer. Potential mechanisms include over-production of chemoattractant and eosinophil-active cytokines (CXCL1, CCL11, CCL3 and IL5) in PVM-infected IFNγ−/− mice; likewise, IFNγ actively antagonized IL5-dependent eosinophil survival ex vivo. Our results may have clinical implications for pneumovirus infection in individuals with IFNγ signaling defects.

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Strain-Dependent Requirement for IFN-γ for Respiratory Control and Immunotherapy in Murine Gammaherpesvirus Infection

Cited by 17 publications

References 40 publications

CD4 and CD8 T Cells Directly Recognize Murine Gammaherpesvirus 68-Immortalized Cells and Prevent Tumor Outgrowth

CD4 and CD8 T Cells Directly Recognize Murine Gammaherpesvirus 68-Immortalized Cells and Prevent Tumor Outgrowth

Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection

Sustained inflammation and differential expression of interferons type I and III in PVM-infected interferon-gamma (IFN γ ) gene-deleted mice

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