Murine Lymphocytic Choriomeningitis Research Articles

The Multifaceted Roles of NK Cells in the Context of Murine Cytomegalovirus and Lymphocytic Choriomeningitis Virus Infections.

NK cells belong to innate lymphoid cells and able to eliminate infected cells and tumor cells. NK cells play a valuable role in controlling viral infections. Also, they have the potential to shape the adaptive immunity via a unique crosstalk with the different immune cells. Murine models are important tools for delineating the immunological phenomena in viral infection. To decipher the immunological virus-host interactions, two major infection models are being investigated in mice regarding NK cell-mediated recognition: murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV). In this review, we recapitulate recent findings regarding the multifaceted role of NK cells in controlling LCMV and MCMV infections and outline the exquisite interplay between NK cells and other immune cells in these two settings. Considering that, infections with MCMV and LCMV recapitulates many physiopathological characteristics of human cytomegalovirus infection and chronic virus infections respectively, this study will extend our understanding of NK cells biology in interactions between the virus and its natural host.

Promyelocytic leukemia protein is a restriction factor for Junín virus independently of Z matrix protein

The New World (NW) mammarenavirus Junín (JUNV) is the etiological agent of Argentine hemorrhagic fever, a human endemic disease of Argentina. Promyelocytic leukemia protein (PML) has been reported as a restriction factor for several viruses although the mechanism/s behind PML-mediated antiviral effect may be diverse and are a matter of debate. Previous studies have reported a nuclear to cytoplasm translocation of PML during the murine Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) infection. This translocation was found to be mediated by the viral Z protein. Here, we show that PML restricts JUNV infection in human A549 cells. However, in contrast to LCVM, JUNV infection enhances PML expression and PML is not translocated to the cytoplasm neither it colocalizes with JUNV Z protein. Our study demonstrates that a NW mammarenavirus as JUNV interacts differently with the antiviral protein PML than LCMV.

Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection.

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

Aging of Antiviral CD8+ Memory T Cells Fosters Increased Survival, Metabolic Adaptations, and Lymphoid Tissue Homing.

Aging of established antiviral T cell memory can foster a series of progressive adaptations that paradoxically improve rather than compromise protective CD8+ T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8+ memory T cell (TM) homeostasis. Over time, CD8+ TM generated in the wake of an acute infection with the natural murine pathogen lymphocytic choriomeningitis virus become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+ TM quiescence and fitness but also impart the reacquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+ TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+ TM accumulations in bone marrow, splenic white pulp, and, particularly, lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8+ TM poised for greater recall responses.

Interleukin-27R Signaling Mediates Early Viral Containment and Impacts Innate and Adaptive Immunity after Chronic Lymphocytic Choriomeningitis Virus Infection.

ABSTRACTChronic viral infections represent a major challenge to the host immune response, and a unique network of immunological elements, including cytokines, are required for their containment. By using a model persistent infection with the natural murine pathogen lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) we investigated the role of one such cytokine, interleukin-27 (IL-27), in the control of chronic infection. We found that IL-27 receptor (IL-27R) signaling promoted control of LCMV Cl13 as early as days 1 and 5 after infection and that il27p28 transcripts were rapidly elevated in multiple subsets of dendritic cells (DCs) and myeloid cells. In particular, plasmacytoid DCs (pDCs), the most potent type 1 interferon (IFN-I)-producing cells, significantly increased il27p28 in a Toll-like receptor 7 (TLR7)-dependent fashion. Notably, mice deficient in an IL-27-specific receptor, WSX-1, exhibited a pleiotropy of innate and adaptive immune alterations after chronic lymphocytic choriomeningitis virus (LCMV) infection, including compromised NK cell cytotoxicity and antibody responses. While, the majority of these immune alterations appeared to be cell extrinsic, cell-intrinsic IL-27R was necessary to maintain early pDC numbers, which, alongside lower IFN-I transcription in CD11b+ DCs and myeloid cells, may explain the compromised IFN-I elevation that we observed early after LCMV Cl13 infection in IL-27R-deficient mice. Together, these data highlight the critical role of IL-27 in enabling optimal antiviral immunity early and late after infection with a systemic persistent virus and suggest that a previously unrecognized positive-feedback loop mediated by IL-27 in pDCs might be involved in this process.IMPORTANCE Persistently replicating pathogens, such as human immunodeficiency virus, hepatitis B virus, and hepatitis C virus, represent major health problems worldwide. These infections impose a long-term challenge on the host immune system, which must be heavily and continuously regulated to keep pathogen replication in check without causing fatal immunopathology. Using a persistently replicating rodent pathogen, LCMV, in its natural host, we identified the cellular sources and effects of one important regulatory pathway, interleukin-27 receptor WSX-1 signaling, that is required for both very early and late restriction of chronic (but not acute) infection. We found that WSX-1 was necessary to promote innate immunity and the development of aberrant adaptive immune responses. This not only highlights the role of IL-27 receptor signaling in regulating distinct host responses that are known to be necessary to control chronic infections, but also positions IL-27 as a potential therapeutic target for their modulation.

Targeting of non-dominant antigens as a vaccine strategy to broaden T-cell responses during chronic viral infection.

In this study, we compared adenoviral vaccine vectors with the capacity to induce equally potent immune responses against non-dominant and immunodominant epitopes of murine lymphocytic choriomeningitis virus (LCMV). Our results demonstrate that vaccination targeting non-dominant epitopes facilitates potent virus-induced T-cell responses against immunodominant epitopes during subsequent challenge with highly invasive virus. In contrast, when an immunodominant epitope was included in the vaccine, the T-cell response associated with viral challenge remained focussed on that epitope. Early after challenge with live virus, the CD8+ T cells specific for vaccine-encoded epitopes, displayed a phenotype typically associated with prolonged/persistent antigenic stimulation marked by high levels of KLRG-1, as compared to T cells reacting to epitopes not included in the vaccine. Notably, this association was lost over time in T cells specific for the dominant T cell epitopes, and these cells were fully capable of expanding in response to a new viral challenge. Overall, our data suggests a potential for broadening of the antiviral CD8+ T-cell response by selecting non-dominant antigens to be targeted by vaccination. In addition, our findings suggest that prior adenoviral vaccination is not likely to negatively impact the long-term and protective immune response induced and maintained by a vaccine-attenuated chronic viral infection.

Platelets: the unsung hero of the immune response

Platelets: the unsung hero of the immune response

The Transcription Factor FoxO1 Sustains Expression of the Inhibitory Receptor PD-1 and Survival of Antiviral CD8+ T Cells during Chronic Infection

Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of Tcell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) invivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1?FoxO1?PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection.

Type I Interferon Protects Antiviral CD8+ T Cells from NK Cell Cytotoxicity

Despite development of new antiviral drugs, viral infections are still a major health problem. The most potent antiviral defense mechanism is the innate production of type I interferon (IFN-I), which not only limits virus replication but also promotes antiviral Tcell immunity through mechanisms, which remain insufficiently studied. Using the murine lymphocytic choriomeningitis virus model system, we show here that IFN-I signaling on Tcells prevented their rapid elimination invivo. Microarray analyses uncovered that IFN-I triggered the expression of selected inhibitory NK-cell-receptor ligands. Consequently, Tcell immunity of IFN-I receptor (IFNAR)-deficient Tcells could be restored by NK cell depletion or in NK-cell-deficient hosts (Nfil3(-/-)). The elimination of Ifnar1(-/-) Tcells was dependent on NK-cell-mediated perforin expression. In summary, we identified IFN-I as a key player regulating the protection of Tcells against regulatory NK cell function.

FoxO1 directly regulates the expression of PD-1 and sustains viral specific CD8+ T cell responses during chronic infection (IRM4P.501)

Abstract Understanding the signaling and transcriptional pathways that regulate the function, survival and homeostasis of CD8+ cytotoxic T lymphocytes (CTLs) during chronic infection is fundamental to the development of therapies to treat chronic infections such as HIV, HSV, and HCV. Of these, the PI3K/AKT/mTOR signaling pathway is of significant interest because it controls T cell differentiation, proliferation, metabolism and survival. We show that during murine chronic lymphocytic choriomeningitis virus (LCMV) infection, chronic antigen stimulation greatly impairs the ability of virus-specific CD8 T cells to activate PI3K/AKT/mTOR signaling in response to TCR and cytokine stimulation, resulting in enhanced nuclear retention of the transcription factor, FoxO1. Therapeutic blockade of the inhibitory PD-1 receptor, which restores antiviral CTL responses, was dependent on increased PI3K/AKT/mTOR activity. FoxO1 expression was critical to sustain virus-specific CTL responses and control viral infection. Lastly, we demonstrate that FoxO1 was both necessary and sufficient to induce the expression of the inhibitory receptor PD-1 on virus-specific CD8 T cells, and therefore represents a critical regulatory factor in balancing effector and exhausted CTL states during chronic infection. These findings highlight a novel role for AKT-FoxO1 pathway in the regulation of exhaustion CTL responses during chronic infection.

Reactive oxygen species delay control of lymphocytic choriomeningitis virus

CD8+ T cells are of critical importance to prevent chronic viral infections because they not only promote virus elimination, but also induce virus mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T cell mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus infected liver and spleen tissue that was triggered by the NADPH oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8+ T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T cell function was elevated in p47phox deficient (Ncf1-/-) mice. In the absence of p47phox, enhanced T cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.

Reactive oxygen species delay control of lymphocytic choriomeningitis virus

Cluster of differentiation (CD)8+ T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8+ T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1−/−) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.

Reactive oxygen species delay control of lymphocytic choriomeningitis virus

Event Abstract Back to Event Reactive oxygen species delay control of lymphocytic choriomeningitis virus Haifeng C. Xu1 and Philipp Lang1* 1 Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University., Germany CD8+ T cells are of critical importance to prevent chronic viral infections because they not only promote virus elimination, but also induce virus mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T cell mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus infected liver and spleen tissue that was triggered by the NADPH oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8+ T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T cell function was elevated in p47phox deficient (Ncf1-/-) mice. In the absence of p47phox, enhanced T cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage. Keywords: Hepatitis, virus, ROS, liver cell damage, CD8+ T cells, Granulocytes Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Adaptive Immunity Citation: Xu HC and Lang P (2013). Reactive oxygen species delay control of lymphocytic choriomeningitis virus. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01095 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Philipp Lang, Department of Gastroenterology, Hepatology and Infectiology, Heinrich Heine University., Duesseldorf, Germany, philipp.lang@gmx.net Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Haifeng C Xu Philipp Lang Google Haifeng C Xu Philipp Lang Google Scholar Haifeng C Xu Philipp Lang PubMed Haifeng C Xu Philipp Lang Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8 + T-cell immunity

Infections with HIV, hepatitis B virus, and hepatitis C virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. It is generally thought that virus-mediated T-cell exhaustion limits T-cell function, thus promoting chronic disease. Here we demonstrate that natural killer (NK) cells have a negative impact on the development of T-cell immunity by using the murine lymphocytic choriomeningitis virus. NK cell-deficient (Nfil3(-/-), E4BP4(-/-)) mice exhibited a higher virus-specific T-cell response. In addition, NK cell depletion caused enhanced T-cell immunity in WT mice, which led to rapid virus control and prevented chronic infection in lymphocytic choriomeningitis virus clone 13- and reduced viral load in DOCILE-infected animals. Further experiments showed that NKG2D triggered regulatory NK cell functions, which were mediated by perforin, and limited T-cell responses. Therefore, we identified an important role of regulatory NK cells in limiting T-cell immunity during virus infection.

Late interleukin-6 promotes T follicular helper cell response and resolution of chronic viral infection (105.8)

Abstract Multiple inhibitory molecules create a profoundly immunuosuppressive environment during chronic viral infections in humans and mice, making generation of effective immunity in this context a challenge. Using murine chronic lymphocytic choriomeningitis virus (LCMV) infection we found that non-hematopoietic cells produced interleukin 6 (IL-6) in a unique biphasic manner, with later IL-6 playing an essential role for viral control. The underlying mechanism involved IL-6 upregulation of the transcription factor BCL6 in virus specific CD4 T cells during chronic (but not acute) infection. This resulted in escalation of T follicular helper cell, germinal center and antibody responses at late stages of chronic infection. Notably, while CD4 T cells showed intact IL6 signaling both early and late after chronic infection only late IL6 stimulation resulted in significant BCL6 up-regulation. Finally ablation of the common IL-6 cytokine family receptor gp130 not only curtailed BCL6 upregulation in CD4 T cells but also reduced their numbers and IL-21 expression in a cell-intrinsic fashion. Our results uncover a novel antiviral strategy that overcomes the immunosuppressive environment to promote CD4 helper functions and safely resolves a persistent infection in vivo. These findings could illuminate new therapies to control viral persistence in humans.

No Significant CTL Cross-Priming by Dendritic Cell-Derived Exosomes during Murine Lymphocytic Choriomeningitis Virus Infection

Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells in culture, but are also present in serum. They contain a wide array of protein ligands on their surface, which has led to the hypothesis that they might mediate intercellular communication. Indeed, data support that exosomes can transfer Ags to dendritic cells (DC), and, interestingly, that these DC can subsequently induce T cell priming or tolerance. We have investigated whether this concept can be expanded to antiviral immunity. We isolated exosomes from supernatant of cultured bone marrow-derived DC (BMDC) that were infected with lymphocytic choriomeningitis virus (LCMV) or loaded with an immunodominant LCMV peptide, and characterized them by flow cytometry upon binding to beads. We then incubated the exosome preparations with BMDC and looked at their potential to activate LCMV gp33-specific naive and memory CD8 T cells. We found that exosomes do not significantly contribute to CD8 T cell cross-priming in vitro. Additionally, exosomes derived from in vitro-infected BMDC did not exhibit significant in vivo priming activity, as evidenced by the lack of protection following exosome vaccination. Thus, DC-derived exosomes do not appear to contribute significantly to CTL priming during acute LCMV infection.

Circulating intercellular adhesion molecule-1 (ICAM-1) as an early and sensitive marker for virus-induced T cell activation.

The effect of systemic virus infection on the level of circulating ICAM-1 (cICAM-1) in serum, and the role of virus-activated T cells in this context, were studied using the murine lymphocytic choriomeningitis virus infection as primary model system. A marked virus-induced elevation in cICAM-1 in serum was revealed, the presence of which coincided with the phase of virus-induced T cell activation. However, high levels of cICAM-1 in serum were observed well before maximal T cell activation could be demonstrated. No increase in cICAM-1 was observed in the serum of infected T cell-deficient nude mice, clearly demonstrating that T cells were mandatory. Analysis of MHC class I and MHC class II-deficient mice revealed that either CD4+ or CD8+ T cells alone are sufficient, despite a markedly reduced inflammatory exudate in the former animals. These results indicate that virus-activated T cells induce shedding of ICAM-1 into the circulation, and this parameter may be used as an early and sensitive marker for immune activation.

Programmed death-1 as a factor in immune exhaustion and activation in HIV infection

The aim of this article is to understand the dual role of programmed death-1 (PD-1) as a physiological negative regulator of T cell activation and a mediator of T cell exhaustion in HIV infection. Studies in the murine lymphocytic choriomeningitis virus model showed that the inhibitory receptor PD-1 was upregulated on the surface of exhausted virus-specific CD8 T cells and mediated a reversible impairment of immune responses. Studies in HIV infection demonstrated that PD-1 was upregulated on HIV-specific CD8 and CD4 T lymphocytes and that its expression correlated with markers of disease progression, mediated a proliferative defect of these cells and increased apoptosis of virus-specific CD8 T cells. Blockade of the PD-1 pathway enhanced HIV-specific T cell responses in vitro. These observations demonstrate an unexpected level of reversibility in HIV-specific T cell impairment. Significant efforts are required to further understanding of the PD-1 pathway. It is essential to delineate when PD-1 expression is the signal of physiologic regulatory mechanisms of activated cells, a mere marker of exhausted cells or a major mediator of functional exhaustion. The respective importance of these components, which could vary according to the stage of infection, will determine the clinical potential for immunotherapeutic intervention and the risk of adverse effects.

Control of Virus-Specific CD8+T-Cell Exhaustion and Immune-Mediated Pathology by E3 Ubiquitin Ligase Cbl-b during Chronic Viral Infection

A characteristic feature in the immune response to many persistent viral infections is the dysfunction or deletion of antigen-specific T cells (exhaustion). This down-regulation of virus-specific T-cell response represents a critical control mechanism that exists within T-cell activation pathways to prevent lethal disease by inappropriate responses against disseminating virus infections. However, the molecular mechanisms by which the immune system determines whether to mount a full response to such infections remain largely unexplored. Here, we have established that in the murine lymphocytic choriomeningitis virus (LCMV) model, induction of the T-cell receptor signaling inhibitor molecule E3 ligase Cbl-b is critically involved in this decision. In particular, our data revealed that Cbl-b controls the program responsible for T-cell tolerance (exhaustion) induction during a chronic viral infection. Thus, Cbl-b(-/-) mice infected with a low dose of LCMV Docile mount a strong CD8(+) T-cell response that rapidly clears the infection, and the animals remain healthy; in contrast, down-regulation of the epitope-specific CD8(+) T-cell population in persistently infected Cbl-b(-/-) mice, compared to that in chronically infected B6 mice, was significantly delayed, and this was associated with increased morbidity and eventual death in nearly 20% of the animals. Interestingly, infection of Cbl-b(-/-) mice with a moderate virus dose resulted in rapid death with 100% mortality by 7 to 8 days after infection, caused by a dysregulated antiviral T-cell response, whereas the infected B6 mice survived and remained healthy. In conclusion, our results suggest that Cbl-b is critically involved in T-cell exhaustion and prevention of lethal disease.

Extralymphatic virus sanctuaries as a consequence of potent T-cell activation

T helper cells can support the functions of CD8+ T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. These viruses often resist complete elimination and remain detectable at sanctuary sites, such as the kidneys and other extralymphatic organs. The mechanisms underlying this persistence are not well understood. Here we show that mice with potent virus-specific T-cell responses have reduced levels and delayed formation of neutralizing antibodies, and these mice fail to clear LCMV from extralymphatic epithelia. Transfer of virus-specific B cells but not virus-specific T cells augmented virus clearance from persistent sites. Virus elimination from the kidneys was associated with the formation of IgG deposits in the interstitial space, presumably from kidney-infiltrating B cells. CD8+ T cells in the kidneys of mice that did not clear virus from this site were activated but showed evidence of exhaustion. Thus, we conclude that in this model of infection, site-specific virus persistence develops as a consequence of potent immune activation coupled with reductions in virus-specific neutralizing antibodies. Our results suggest that sanctuary-site formation depends both on organ anatomy and on the induction of different adaptive immune effector mechanisms. Boosting T-cell responses alone may not reduce virus persistence.Supplementary informationThe online version of this article (doi:10.1038/nm1670) contains supplementary material, which is available to authorized users.