Publications by authors named "Taeg S Kim"

24 Publications

  • Page 1 of 1

Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice.

JCI Insight 2017 01 26;2(2):e88257. Epub 2017 Jan 26.

Center for Brain Immunology and Glia.

Loss of function or overexpression of methyl-CpG-binding protein 2 (MeCP2) results in the severe neurodevelopmental disorders Rett syndrome and MeCP2 duplication syndrome, respectively. MeCP2 plays a critical role in neuronal function and the function of cells throughout the body. It has been previously demonstrated that MeCP2 regulates T cell function and macrophage response to multiple stimuli, and that immune-mediated rescue imparts significant benefit in -null mice. Unlike Rett syndrome, MeCP2 duplication syndrome results in chronic, severe respiratory infections, which represent a significant cause of patient morbidity and mortality. Here, we demonstrate that MeCP2 mice, which overexpress MeCP2 at levels 3- to 5-fold higher than normal, are hypersensitive to influenza A/PR/8/34 infection. Prior to death, MeCP2 mice experienced a host of complications during infection, including neutrophilia, increased cytokine production, excessive corticosterone levels, defective adaptive immunity, and vascular pathology characterized by impaired perfusion and pulmonary hemorrhage. Importantly, we found that radioresistant cells are essential to infection-related death after bone marrow transplantation. In all, these results demonstrate that influenza A infection in MeCP2 mice results in pathology affecting both immune and nonhematopoietic cells, suggesting that failure to effectively respond and clear viral respiratory infection has a complex, multicompartment etiology in the context of MeCP2 overexpression.
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http://dx.doi.org/10.1172/jci.insight.88257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256138PMC
January 2017

Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells.

PLoS Pathog 2017 01 13;13(1):e1006140. Epub 2017 Jan 13.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America.

The Influenza A virus (IAV) is a major human pathogen that produces significant morbidity and mortality. To explore the contribution of alveolar macrophages (AlvMΦs) in regulating the severity of IAV infection we employed a murine model in which the Core Binding Factor Beta gene is conditionally disrupted in myeloid cells. These mice exhibit a selective deficiency in AlvMΦs. Following IAV infection these AlvMΦ deficient mice developed severe diffuse alveolar damage, lethal respiratory compromise, and consequent lethality. Lethal injury in these mice resulted from increased infection of their Type-1 Alveolar Epithelial Cells (T1AECs) and the subsequent elimination of the infected T1AECs by the adaptive immune T cell response. Further analysis indicated AlvMΦ-mediated suppression of the cysteinyl leukotriene (cysLT) pathway genes in T1AECs in vivo and in vitro. Inhibition of the cysLT pathway enzymes in a T1AECs cell line reduced the susceptibility of T1AECs to IAV infection, suggesting that AlvMΦ-mediated suppression of this pathway contributes to the resistance of T1AECs to IAV infection. Furthermore, inhibition of the cysLT pathway enzymes, as well as blockade of the cysteinyl leukotriene receptors in the AlvMΦ deficient mice reduced the susceptibility of their T1AECs to IAV infection and protected these mice from lethal infection. These results suggest that AlvMΦs may utilize a previously unappreciated mechanism to protect T1AECs against IAV infection, and thereby reduce the severity of infection. The findings further suggest that the cysLT pathway and the receptors for cysLT metabolites represent potential therapeutic targets in severe IAV infection.
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http://dx.doi.org/10.1371/journal.ppat.1006140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5268648PMC
January 2017

Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cells.

J Clin Invest 2015 Oct 21;125(10):3965-80. Epub 2015 Sep 21.

Erythropoiesis is an important response to certain types of stress, including hypoxia, hemorrhage, bone marrow suppression, and anemia, that result in inadequate tissue oxygenation. This stress-induced erythropoiesis is distinct from basal red blood cell generation; however, neither the cellular nor the molecular factors that regulate this process are fully understood. Here, we report that type 1 conventional dendritic cells (cDC1s), which are defined by expression of CD8α in the mouse and XCR1 and CLEC9 in humans, are critical for induction of erythropoiesis in response to stress. Specifically, using murine models, we determined that engagement of a stress sensor, CD24, on cDC1s upregulates expression of the Kit ligand stem cell factor on these cells. The increased expression of stem cell factor resulted in Kit-mediated proliferative expansion of early erythroid progenitors and, ultimately, transient reticulocytosis in the circulation. Moreover, this stress response was triggered in part by alarmin recognition and was blunted in CD24 sensor- and CD8α+ DC-deficient animals. The contribution of the cDC1 subset to the initiation of stress erythropoiesis was distinct from the well-recognized role of macrophages in supporting late erythroid maturation. Together, these findings offer insight into the mechanism of stress erythropoiesis and into disorders of erythrocyte generation associated with stress.
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http://dx.doi.org/10.1172/JCI81919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607133PMC
October 2015

IL-21R signaling suppresses IL-17+ gamma delta T cell responses and production of IL-17 related cytokines in the lung at steady state and after Influenza A virus infection.

PLoS One 2015 7;10(4):e0120169. Epub 2015 Apr 7.

The Beirne B. Carter Center for Immunology Research, The University of Virginia, Charlottesville, Virginia, United States of America; Department of Pathology, The University of Virginia, Charlottesville, Virginia, United States of America.

Influenza A virus (IAV) infection of the respiratory tract elicits a robust immune response, which is required for efficient virus clearance but at the same time can contribute to lung damage and enhanced morbidity. IL-21 is a member of the type I cytokine family and has many different immune-modulatory functions during acute and chronic virus infections, although its role in IAV infection has not been fully evaluated. In this report we evaluated the contributions of IL-21/IL-21 receptor (IL-21R) signaling to host defense in a mouse model of primary IAV infection using IL-21R knock out (KO) mice. We found that lack of IL-21R signaling had no significant impact on virus clearance, adaptive T cell responses, or myeloid cell accumulations in the respiratory tract. However, a subset of inflammatory cytokines were elevated in the bronchoalveolar lavage fluid of IL-21R KO mice, including IL-17. Although there was only a small increase in Th17 cells in the lungs of IL-21R KO mice, we observed a dramatic increase in gamma delta (γδ) T cells capable of producing IL-17 both after IAV infection and at steady state in the respiratory tract. Finally, we found that IL-21R signaling suppressed the accumulation of IL-17+ γδ T cells in the respiratory tract intrinsically. Thus, our study reveals a previously unrecognized role of IL-21R signaling in regulating IL-17 production by γδ T cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120169PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388622PMC
April 2016

Liver-resident CD103+ dendritic cells prime antiviral CD8+ T cells in situ.

J Immunol 2015 Apr 23;194(7):3213-22. Epub 2015 Feb 23.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908; Department of Microbiology, University of Virginia, Charlottesville, VA 22908;

The liver maintains a tolerogenic environment to avoid unwarranted activation of its resident immune cells upon continuous exposure to food and bacterially derived Ags. However, in response to hepatotropic viral infection, the liver's ability to switch from a hyporesponsive to a proinflammatory environment is mediated by select sentinels within the parenchyma. To determine the contribution of hepatic dendritic cells (DCs) in the activation of naive CD8(+) T cells, we first characterized resident DC subsets in the murine liver. Liver DCs exhibit unique properties, including the expression of CD8α (traditionally lymphoid tissue specific), CD11b, and CD103 markers. In both the steady-state and following viral infection, liver CD103(+) DCs express high levels of MHC class II, CD80, and CD86 and contribute to the high number of activated CD8(+) T cells. Importantly, viral infection in the Batf3(-/-) mouse, which lacks CD8α(+) and CD103(+) DCs in the liver, results in a 3-fold reduction in the proliferative response of Ag-specific CD8(+) T cells. Limiting DC migration out of the liver does not significantly alter CD8(+) T cell responsiveness, indicating that CD103(+) DCs initiate the induction of CD8(+) T cell responses in situ. Collectively, these data suggest that liver-resident CD103(+) DCs are highly immunogenic in response to hepatotropic viral infection and serve as a major APC to support the local CD8(+) T cell response. It also implies that CD103(+) DCs present a promising cellular target for vaccination strategies to resolve chronic liver infections.
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http://dx.doi.org/10.4049/jimmunol.1402622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369411PMC
April 2015

Unexpected phenotype of mice lacking Shcbp1, a protein induced during T cell proliferation.

PLoS One 2014 25;9(8):e105576. Epub 2014 Aug 25.

Department of Microbiology, Immunology, Cancer biology, University of Virginia, Charlottesville, Virginia, United States of America; Carter Immunology Center, University of Virginia, Charlottesville, Virginia, United States of America; Center for Cell Clearance, University of Virginia, Charlottesville, Virginia, United States of America.

T cell development and activation are highly regulated processes, and their proper execution is important for a competent immune system. Shc SH2-domain binding protein-1 (Shcbp1) is an evolutionarily conserved protein that binds to the adaptor protein ShcA. Studies in Drosophila and in cell lines have strongly linked Shcbp1 to cell proliferation, embryonic development, growth factor signaling, and tumorigenesis. Here we show that Shcbp1 expression is strikingly upregulated during the β-selection checkpoint in thymocytes, and that its expression tightly correlates with proliferative stages of T cell development. To evaluate the role for Shcbp1 during thymic selection and T cell function in vivo, we generated mice with global and conditional deletion of Shcbp1. Surprisingly, the loss of Shcbp1 expression did not have an obvious effect during T cell development. However, in a mouse model of experimental autoimmune encephalomyelitis (EAE), which depends on CD4(+) T cell function and mimics multiple features of the human disease multiple sclerosis, Shcbp1 deficient mice had reduced disease severity and improved survival, and this effect was T cell intrinsic. These data suggest that despite the striking upregulation of Shcbp1 during T cell proliferation, loss of Shcbp1 does not directly affect T cell development, but regulates CD4(+) T cell effector function in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105576PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143286PMC
November 2015

The effector T cell response to influenza infection.

Curr Top Microbiol Immunol 2015 ;386:423-55

Department of Pediatrics, Indiana University School of Medicine, Indianapolis, USA.

Influenza virus infection induces a potent initial innate immune response, which serves to limit the extent of viral replication and virus spread. However, efficient (and eventual) viral clearance within the respiratory tract requires the subsequent activation, rapid proliferation, recruitment, and expression of effector activities by the adaptive immune system, consisting of antibody producing B cells and influenza-specific T lymphocytes with diverse functions. The ensuing effector activities of these T lymphocytes ultimately determine (along with antibodies) the capacity of the host to eliminate the viruses and the extent of tissue damage. In this review, we describe this effector T cell response to influenza virus infection. Based on information largely obtained in experimental settings (i.e., murine models), we will illustrate the factors regulating the induction of adaptive immune T cell responses to influenza, the effector activities displayed by these activated T cells, the mechanisms underlying the expression of these effector mechanisms, and the control of the activation/differentiation of these T cells, in situ, in the infected lungs.
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http://dx.doi.org/10.1007/82_2014_397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224975PMC
March 2015

Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism.

Immunity 2014 Mar 13;40(3):400-13. Epub 2014 Mar 13.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia, Charlottesville, VA 22908, USA; Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

The contribution of different DC subsets to effector and memory CD8(+) T cell generation during infection and the mechanism by which DCs controls these fate decisions is unclear. Here we demonstrated that the CD103(+) and CD11b(hi) migratory respiratory DC (RDC) subsets after influenza virus infection activated naive virus-specific CD8(+) T cells differentially. CD103(+) RDCs supported the generation of CD8(+) T effector (Teff) cells, which migrate from lymph nodes to the infected lungs. In contrast, migrant CD11b(hi) RDCs activated CD8(+) T cells characteristic of central memory CD8(+) T (CD8(+) Tcm) cells including retention within the draining lymph nodes. CD103(+) RDCs expressed CD24 at an elevated level, contributing to the propensity of this DC subpopulation to support CD8(+) Teff cell differentiation. Mechanistically, CD24 was shown to regulate CD8(+) T cell activation through HMGB1-mediated engagement of T cell RAGE. Thus, there is distribution of labor among DC subsets in regulating CD8(+) T cell differentiation.
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http://dx.doi.org/10.1016/j.immuni.2014.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017923PMC
March 2014

Viral infection of the lung: host response and sequelae.

J Allergy Clin Immunol 2013 Dec 1;132(6):1263-76; quiz 1277. Epub 2013 Aug 1.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Va.

Because of its essential role in gas exchange and oxygen delivery, the lung has evolved a variety of strategies to control inflammation and maintain homeostasis. Invasion of the lung by pathogens (and in some instances exposure to certain noninfectious particulates) disrupts this equilibrium and triggers a cascade of events aimed at preventing or limiting colonization (and more importantly infection) by pathogenic microorganisms. In this review we focus on viral infection of the lung and summarize recent advances in our understanding of the triggering of innate and adaptive immune responses to viral respiratory tract infection, mechanisms of viral clearance, and the well-recognized consequences of acute viral infection complicating underlying lung diseases, such as asthma.
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http://dx.doi.org/10.1016/j.jaci.2013.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844062PMC
December 2013

Regulating the adaptive immune response to respiratory virus infection.

Nat Rev Immunol 2012 Mar 9;12(4):295-305. Epub 2012 Mar 9.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.

Recent years have seen several advances in our understanding of immunity to virus infection of the lower respiratory tract, including to influenza virus infection. Here, we review the cellular targets of viruses and the features of the host immune response that are unique to the lungs. We describe the interplay between innate and adaptive immune cells in the induction, expression and control of antiviral immunity, and discuss the impact of the infected lung milieu on moulding the response of antiviral effector T cells. Recent findings on the mechanisms that underlie the increased frequency of severe pulmonary bacterial infections following respiratory virus infection are also discussed.
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http://dx.doi.org/10.1038/nri3166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364025PMC
March 2012

Slowing down with age: lung DCs do it too.

J Clin Invest 2011 Dec 21;121(12):4636-9. Epub 2011 Nov 21.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.

Decline in immune function with age has been attributed to defects or alterations in both the innate and the adaptive immune system. In this issue of the JCI, Zhao and coworkers provide evidence for a novel mechanism of immune dysfunction in aging mice. They show that migration of respiratory DCs from the site of virus replication to the draining lymph nodes in response to infection with several different respiratory viruses is markedly diminished with increasing age. The impaired DC migration was a result of increased levels of the lipid mediator prostaglandin D(2) (PGD(2)) in the respiratory tract with age and could be partially reversed by blockade of PGD(2) synthesis or action.
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http://dx.doi.org/10.1172/JCI61367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226069PMC
December 2011

T cell responses during influenza infection: getting and keeping control.

Trends Immunol 2011 May 23;32(5):225-31. Epub 2011 Mar 23.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.

The 2009 influenza pandemic highlighted the threat that type A influenza poses to human health. Thus, there is an urgency to understand the pathobiology of influenza infection and the contribution of the host immune response to virus elimination and the development of lung injury. This review focuses on the T cell arm of the adaptive host immune response to influenza. We assess recent developments in the understanding of how primary influenza virus-specific T cell responses are induced by antigen-presenting cells, the interaction of activated effector T cells with antigen-bearing cells in the infected lungs. Also examined is the contribution of influenza-specific effector T cells to the development and control of lung injury and inflammation during infection.
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http://dx.doi.org/10.1016/j.it.2011.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090469PMC
May 2011

Antiviral CD8+ T cell effector activities in situ are regulated by target cell type.

J Exp Med 2011 Jan 27;208(1):167-80. Epub 2010 Dec 27.

Beirne B. Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, VA 22904, USA.

Cytotoxic T lymphocytes (CTLs) play a prominent role in the resolution of viral infections through their capacity both to mediate contact-dependent lysis of infected cells and to release soluble proinflammatory cytokines and chemokines. The factors controlling these antiviral effector activities in vivo at infection sites are ill defined. Using a mouse model of influenza infection, we observed that the expression of CTL effector activity in the infected lungs is dictated by the target cell type encountered. CD45(+) lung infiltrating inflammatory mononuclear cells, particularly CD11c(hi) dendritic cells, trigger both CTL cytotoxicity and release of inflammatory mediators, whereas CD45(-) influenza-infected respiratory epithelial cells stimulate only CTL cytotoxicity. CTL proinflammatory mediator release is modulated by co-stimulatory ligands (CD80 and CD86) expressed by the CD45(+) inflammatory cells. These findings suggest novel mechanisms of control of CTL effector activity and have potentially important implications for the control of excess pulmonary inflammation and immunopathology while preserving optimal viral clearance during respiratory virus infections.
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http://dx.doi.org/10.1084/jem.20101850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023137PMC
January 2011

The cell cycle time of CD8+ T cells responding in vivo is controlled by the type of antigenic stimulus.

PLoS One 2010 Nov 8;5(11):e15423. Epub 2010 Nov 8.

The Carter Immunology Center, University of Virginia, Charlottesville, Virginia, United States of America.

A hallmark of cells comprising the mammalian adaptive immune system is the requirement for these rare naïve T (and B) lymphocytes directed to a specific microorganism to undergo proliferative expansion upon first encounter with this antigen. In the case of naïve CD8(+) T cells the ability of these rare quiescent lymphocytes to rapidly activate and expand into effector T cells in numbers sufficient to control viral and certain bacterial infections can be essential for survival. In this report we examined the activation, cell cycle time and initial proliferative response of naïve murine CD8(+) T cells responding in vivo to Influenza and Vaccinia virus infection or vaccination with viral antigens. Remarkably, we observed that CD8(+) T cells could divide and proliferate with an initial cell division time of as short as 2 hours. The initial cell cycle time of responding CD8(+) T cells is not fixed but is controlled by the antigenic stimulus provided by the APC in vivo. Initial cell cycle time influences the rate of T cell expansion and the numbers of effector T cells subsequently accumulating at the site of infection. The T cell cycle time varies with duration of the G(1) phase of the cell cycle. The duration of G(1) is inversely correlated with the phosphorylation state of the retinoblastoma (Rb) protein in the responding T cells. The implication of these findings for the development of adaptive immune responses and the regulation of cell cycle in higher eukaryotic cells is discussed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975678PMC
November 2010

Antigen persistence and the control of local T cell memory by migrant respiratory dendritic cells after acute virus infection.

J Exp Med 2010 Jun 31;207(6):1161-72. Epub 2010 May 31.

Beirne B. Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.

Acute viral infections induce robust adaptive immune responses resulting in virus clearance. Recent evidence suggests that there may be depots of viral antigen that persist in draining lymph nodes (DLNs) after virus clearance and could, therefore, affect the adaptive immune response and memory T cell formation. The nature of these residual antigen depots, the mechanism of antigen persistence, and the impact of the persistent antigen on memory T cells remain ill defined. Using a mouse model of influenza virus infection of the respiratory tract, we identified respiratory dendritic cells (RDCs) as essential for both sampling and presenting residual viral antigen. RDCs in the previously infected lung capture residual viral antigen deposited in an irradiation-resistant cell type. RDCs then transport the viral antigen to the LNs draining the site of infection, where they present the antigen to T cells. Lastly, we document preferential localization of memory T cells to the DLNs after virus clearance as a consequence of presentation of residual viral antigen by the migrant RDC.
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http://dx.doi.org/10.1084/jem.20092017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882836PMC
June 2010

Liver is able to activate naïve CD8+ T cells with dysfunctional anti-viral activity in the murine system.

PLoS One 2009 Oct 30;4(10):e7619. Epub 2009 Oct 30.

Beirne Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, Virginia, USA.

The liver possesses distinct tolerogenic properties because of continuous exposure to bacterial constituents and nonpathogenic food antigen. The central immune mediators required for the generation of effective immune responses in the liver environment have not been fully elucidated. In this report, we demonstrate that the liver can indeed support effector CD8(+) T cells during adenovirus infection when the T cells are primed in secondary lymphoid tissues. In contrast, when viral antigen is delivered predominantly to the liver via intravenous (IV) adenovirus infection, intrahepatic CD8(+) T cells are significantly impaired in their ability to produce inflammatory cytokines and lyse target cells. Additionally, intrahepatic CD8(+) T cells generated during IV adenovirus infection express elevated levels of PD-1. Notably, lower doses of adenovirus infection do not rescue the impaired effector function of intrahepatic CD8(+) T cell responses. Instead, intrahepatic antigen recognition limits the generation of potent anti-viral responses at both priming and effector stages of the CD8(+) T cell response and accounts for the dysfunctional CD8(+) T cell response observed during IV adenovirus infection. These results also implicate that manipulation of antigen delivery will facilitate the design of improved vaccination strategies to persistent viral infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2764869PMC
October 2009

Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses.

PLoS One 2009 15;4(1):e4204. Epub 2009 Jan 15.

Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America.

Dendritic cells located at the body surfaces, e.g. skin, respiratory and gastrointestinal tract, play an essential role in the induction of adaptive immune responses to pathogens and inert antigens present at these surfaces. In the respiratory tract, multiple subsets of dendritic cells (RDC) have been identified in both the normal and inflamed lungs. While the importance of RDC in antigen transport from the inflamed or infected respiratory tract to the lymph nodes draining this site is well recognized, the contribution of individual RDC subsets to this process and the precise role of migrant RDC within the lymph nodes in antigen presentation to T cells is not clear. In this report, we demonstrate that two distinct subsets of migrant RDC--exhibiting the CD103(+) and CD11b(hi) phenotype, respectively--are the primary DC presenting antigen to naïve CD4(+) and CD8(+) T lymphocytes in the draining nodes in response to respiratory influenza virus infection. Furthermore, the migrant CD103(+) RDC subset preferentially drives efficient proliferation and differentiation of naive CD8(+) T cells responding to infection into effector cells, and only the CD103(+) RDC subset can present to naïve CD8(+) T cells non-infectious viral vaccine introduced into the respiratory tract. These results identify CD103(+) and CD11b(hi) RDC as critical regulators of the adaptive immune response to respiratory tract infection and potential targets in the design of mucosal vaccines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0004204PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2615220PMC
March 2009

Differential response of respiratory dendritic cell subsets to influenza virus infection.

J Virol 2008 May 19;82(10):4908-19. Epub 2008 Mar 19.

Carter Immunology Center, UVA, P.O. Box 801386, Charlottesville, VA 22908, USA.

Dendritic cells (DC) are believed to play an important role in the initiation of innate and adaptive immune responses to infection, including respiratory tract infections, where respiratory DC (RDC) perform this role. In this report, we examined the susceptibilities of isolated murine RDC to influenza virus infection in vitro and the effect of the multiplicity of infection (MOI) on costimulatory ligand upregulation and inflammatory cytokine/chemokine production after infection. We found that the efficiency of influenza virus infection of RDC increased with increasing MOIs. Furthermore, distinct subpopulations of RDC differed in their susceptibilities to influenza virus infection and in the magnitude/tempo of costimulatory ligand expression. Additional characterization of the CD11c-positive (CD11c(+)) RDC revealed that the identifiable subsets of RDC differed in susceptibility to infection, with CD11c(+) CD103(+) DC exhibiting the greatest susceptibility, CD11c(+) CD11b(hi) DC exhibiting intermediate susceptibility, and CD11c(+) B220(+) plasmacytoid DC (pDC) exhibiting the least susceptibility to infection. A companion analysis of the in vivo susceptibilities of these RDC subsets to influenza virus revealed a corresponding infection pattern. The three RDC subsets displayed different patterns of cytokine/chemokine production in response to influenza virus infection in vitro: pDC were the predominant producers of most cytokines examined, while CD103(+) DC and CD11b(hi) DC produced elevated levels of the murine chemokine CXCL1 (KC), interleukin 12p40, and RANTES in response to influenza virus infection. Our results indicate that RDC are targets of influenza virus infection and that distinct RDC subsets differ in their susceptibilities and responses to infection.
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http://dx.doi.org/10.1128/JVI.02367-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2346724PMC
May 2008

Maturation and localization of macrophages and microglia during infection with a neurotropic murine coronavirus.

Brain Pathol 2008 Jan 12;18(1):40-51. Epub 2007 Oct 12.

University of Iowa, Iowa City, IA, USA.

Macrophages and microglia are critical in the acute inflammatory response and act as final effector cells of demyelination during chronic infection with the neutrotropic MHV-JHM strain of mouse hepatitis virus (MHV-JHM). Herein, we show that "immature" F4/80(+)Ly-6C(hi) monocytes are the first cells, along with neutrophils, to enter the MHV-JHM-infected central nervous system (CNS). As the infection progresses, macrophages in the CNS down-regulate expression of Ly-6C and CD62L, consistent with maturation, and a higher frequency express CD11c, a marker for dendritic cells (DCs). Microglia also express CD11c during this phase of the infection. CD11c(+) macrophages in the infected CNS exhibit variable properties of immature antigen-presenting cells (APCs), with modestly increased CD40 and MHC expression, and equivalent potent antigen uptake when compared with CD11c(-) macrophages. Furthermore, CDllc(+) and F4/80(+) macrophages and microglia are localized to areas of demyelination, in some instances directly associated with damaged axons. These results suggest that chronic CNS infection results in the appearance of CD11c-expressing macrophages from the blood that exhibit properties of immature APCs, are closely associated with areas of demyelination, and may act as final effectors of myelin destruction.
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http://dx.doi.org/10.1111/j.1750-3639.2007.00098.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596182PMC
January 2008

Detection and quantitation of eosinophils in the murine respiratory tract by flow cytometry.

J Immunol Methods 2007 Oct 8;327(1-2):63-74. Epub 2007 Aug 8.

The Carter Immunology Center, UVA Health Sciences Center, Charlottesville, VA 22908, United States.

Traditionally, the identification and quantification of eosinophils in inflammatory tissues and exudates has been primarily based upon morphologic criteria and manual counting. In this study, we describe a new flow cytometry-based assay to enumerate eosinophils present in murine bronchoalveolar lavage fluid (BAL) and lung parenchyma obtained from the normal/non-inflamed respiratory tract, following experimentally-induced allergic pulmonary inflammation, and during experimental infection with respiratory syncytial virus (RSV). By using a murine Siglec-F-specific antibody in combination with antibodies directed to CD45 and CD11c, we demonstrate that eosinophils can be distinguished from other cell types in the BAL fluid and lung parenchyma based upon their distinct CD45(+) Siglec-F(+) and CD11c(low/-) staining profile. In the BAL fluid, this flow cytometry-based method of eosinophil identification/quantitation yields results comparable to the standard morphology-based method without the potential observer bias or staining artifacts inherent in morphology-based quantitation. Furthermore, this flow cytometry-based method can be directly adapted to enumerate eosinophils infiltrating the inflamed lung parenchyma, thereby obviating the need for quantitative morphometry of tissue sections.
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http://dx.doi.org/10.1016/j.jim.2007.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670191PMC
October 2007

Viral expression of CCL2 is sufficient to induce demyelination in RAG1-/- mice infected with a neurotropic coronavirus.

J Virol 2005 Jun;79(11):7113-20

Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.

Mouse hepatitis virus strain JHM causes a chronic demyelinating disease in susceptible strains of rodents. Demyelination does not develop in infected RAG1-/- (recombination activation gene-deficient) mice but can be induced by several experimental interventions, including adoptive transfer of virus-specific T cells or antibodies. A common feature of demyelination in these models is extensive infiltration of macrophages/microglia into the white matter. The data obtained thus far do not indicate whether macrophage/microglia infiltration, in the absence of T cells or antibody, is sufficient to mediate demyelination. To determine whether the expression of a single macrophage chemoattractant, in the context of virus infection, could initiate the demyelinating process, we engineered a recombinant coronavirus that expressed the chemokine CCL2/monocyte chemoattractant protein-1. CCL2 has been implicated in macrophage infiltration into the central nervous system and is involved in demyelination in many experimental models of demyelination. Extensive macrophage/microglia infiltration and demyelination has developed in RAG1-/- mice infected with this recombinant virus. Thus, these results suggest that the minimal requirement for demyelination is increased expression of a single macrophage-attracting chemokine in the context of an inflammatory milieu, such as that induced by a viral infection.
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http://dx.doi.org/10.1128/JVI.79.11.7113-7120.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1112157PMC
June 2005

Virus-specific antibody, in the absence of T cells, mediates demyelination in mice infected with a neurotropic coronavirus.

Am J Pathol 2005 Mar;166(3):801-9

Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.

Mice infected with mouse hepatitis virus strain JHM develop an inflammatory demyelinating disease in the central nervous system with many similarities to human multiple sclerosis. The mouse disease is primarily immune-mediated because demyelination is not detected in JHM-infected mice lacking T or B cells but does occur after transfer of JHM-specific T cells. Although less is known about the ability of antibodies to mediate demyelination, the presence of oligoclonally expanded B cells and high concentrations of antibodies (against self or infectious agents) in the central nervous system of many multiple sclerosis patients suggests that antibodies may also contribute to myelin destruction. Here, we show that anti-JHM antibodies, in the absence of T or B cells, caused demyelination in JHM-infected mice. Anti-JHM antibody was detected adjacent to areas of demyelination, consistent with a direct interaction between antibody and infected cells. Demyelination was reduced by 85 to 90% in infected RAG1(-/-) mice lacking normal expression of activating Fc receptors (FcRgamma(-/-)) and by approximately 76% when complement was depleted by treatment with cobra venom factor. These data demonstrate that JHM-specific antibodies are sufficient to cause demyelination and that myelin destruction in the presence of anti-virus antibodies results from a combination of complement- and Fc receptor-dependent mechanisms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602352PMC
http://dx.doi.org/10.1016/S0002-9440(10)62301-2DOI Listing
March 2005

Enhanced virulence mediated by the murine coronavirus, mouse hepatitis virus strain JHM, is associated with a glycine at residue 310 of the spike glycoprotein.

J Virol 2003 Oct;77(19):10260-9

Interdisciplinary Program in Immunology, University of Iowa, Iowa City, Iowa 52242, USA.

The coronavirus, mouse hepatitis virus strain JHM, causes acute and chronic neurological diseases in rodents. Here we demonstrate that two closely related virus variants, both of which cause acute encephalitis in susceptible strains of mice, cause markedly different diseases if mice are protected with a suboptimal amount of an anti-JHM neutralizing antibody. One strain, JHM.SD, caused acute encephalitis, while infection with JHM.IA resulted in no acute disease. Using recombinant virus technology, we found that the differences between the two viruses mapped to the spike (S) glycoprotein and that the two S proteins differed at four amino acids. By engineering viruses that differed by only one amino acid, we identified a serine-to-glycine change at position 310 of the S protein (S310G) that recapitulated the more neurovirulent phenotype. The increased neurovirulence mediated by the virus encoding glycine at position S310 was not associated with a different tropism within the central nervous system (CNS) but was associated with increased lateral spread in the CNS, leading to significantly higher brain viral titers. In vitro studies revealed that S310G was associated with decreased S1-S2 stability and with enhanced ability to mediate infection of cells lacking the primary receptor for JHM ("receptor-independent spread"). These enhanced fusogenic properties of viruses encoding a glycine at position 310 of the S protein may contribute to spread within the CNS, a tissue in which expression of conventional JHM receptors is low.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC228498PMC
http://dx.doi.org/10.1128/jvi.77.19.10260-10269.2003DOI Listing
October 2003

Protection against CTL escape and clinical disease in a murine model of virus persistence.

J Immunol 2003 Aug;171(4):2006-13

Interdisciplinary Program in Immunology, Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.

CTL escape mutations have been identified in several chronic infections, including mice infected with mouse hepatitis virus strain JHM. One outstanding question in understanding CTL escape is whether a CD8 T cell response to two or more immunodominant CTL epitopes would prevent CTL escape. Although CTL escape at multiple epitopes seems intuitively unlikely, CTL escape at multiple CD8 T cell epitopes has been documented in some chronically infected individual animals. To resolve this apparent contradiction, we engineered a recombinant variant of JHM that expressed the well-characterized gp33 epitope of lymphocytic choriomeningitis virus, an epitope with high functional avidity. The results show that the presence of a host response to this second epitope protected mice against CTL escape at the immunodominant JHM-specific CD8 T cell epitope, the persistence of infectious virus, and the development of clinical disease.
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http://dx.doi.org/10.4049/jimmunol.171.4.2006DOI Listing
August 2003