Role of Lymphocytic Choriomeningitis Virus (LCMV) in Understanding Viral Immunology: Past, Present and Future

Zhou, Xin; Ramachandran, Srividya; Mann, Margaret; Popkin, Daniel L.

doi:10.3390/v4112650

Cited by 107 publications

(76 citation statements)

References 105 publications

(102 reference statements)

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“…To determine how the abundance of specific Tregs relates to the effectiveness of pathogen clearance, we used the mouse model of LCMV to track Treg response following infection (28). This model was selected because acute or chronic infection can be induced by viral strains that differ only by 2 amino acids that do not affect the relevant T-cell epitopes (29). Thus, the same specific T cells can be examined in distinct infectious contexts and at different time points to provide information on Tregs dynamics following acute or chronic viral exposure.…”

Section: Lcmv Infection Reduces Gp66-specific Tregs and Inversely Cormentioning

confidence: 99%

Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

Alcazar

Stelekati

et al. 2016

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

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The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide-MHC tetramers, we isolated rare specific Foxp3 + cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. We find that a proportion of circulating Tregs recognize foreign antigens and the frequency of these cells are similar to that of selfreactive Tregs in the absence of cognate infection. In contrast, the frequencies of Tregs that recognize some common microbial antigens are significantly reduced in the blood of most adults. Exposure to peripheral antigens likely has a major influence on the balance between Tregs and conventional T-cell subsets because a larger proportion of flu-specific T cells has a regulatory cell phenotype in the cord blood. Consistent with this finding, we show that lymphocytic choriomeningitis virus infection can directly modulate the ratio of virus-specific effectors and Tregs in mice. The resulting change in the balance within an antigen-specific T-cell population further correlates with the magnitude of effector response and the chronicity of infection. Taken together, our data highlight the importance of antigen specificity in the functional dynamics of the T-cell repertoire. Each specific population of CD4 + T cells in human peripheral blood contains a subset of Tregs at birth, but the balance between regulatory and effector subsets changes in response to peripheral antigen exposure and this could impact the robustness of antipathogen immunity.regulatory T cells | antigen specificity | repertoire | human | influenza

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Section: Lcmv Infection Reduces Gp66-specific Tregs and Inversely Cormentioning

confidence: 99%

Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

Alcazar

Stelekati

et al. 2016

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

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“…Lymphocytic choriomeningitis virus (LCMV) is a widely used disease model for studies of the immune response to viral infection (6). LCMV-Armstrong (Arm), first described in the 1930s after an encephalitis epidemic in St. Louis, Missouri (7), results in an acute viral infection, the rapid resolution of which depends largely on an efficient, virus-specific CD8 + cytotoxic T-cell response.…”

mentioning

confidence: 99%

Genetic disruption of CD8 ⁺ Treg activity enhances the immune response to viral infection

Holderried

Lang

Kim

et al. 2013

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

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The immunological interactions that regulate the T-cell response to chronic viral infection are insufficiently understood. Here we study a cellular interaction that may enhance the antiviral immune response and constrain immunopathology. We analyze the contribution of Qa-1-restricted CD8 + regulatory T cells (Treg cells) to antiviral immunity after infection by lymphocytic choriomeningitis virus. These CD8 + Treg cells recognize and eliminate target cells through an interaction with the murine class Ib MHC molecule Qa-1 (HLA-E in humans). Using Qa-1 mutant mice (B6.Qa-1-D227K [B6-DK]) that harbor a single mutation that abrogates binding of Qa-1 peptide to the CD8-TCR (T-cell receptor) complex, we show that disruption of immune suppression mediated by CD8+ Treg cells results in robust antiviral immune responses in both acute and chronic viral infection. Enhanced antiviral responses of B6-DK mice were accompanied by increased control of virus, reduced tissue inflammation in the acute phase, and dramatic alleviation of disease in the chronic phase. In addition, CD8+ effector T cells in B6-DK mice displayed a less exhausted phenotype characterized by decreased expression of programmed cell death 1 (PD-1), LAG3 (CD223), and 2B4 (CD244) and increased expression of NKG2D (CD314) and killer cell lectin-like receptor subfamily G member 1 (KLRG1). Enhanced antiviral immunity in B6-DK mice reflected, in part, reduced inhibition of CD8 + effector cells by CD8 + Treg cells. These findings indicate that direct inhibition of effector CD8 + T cells by Qa-1-restricted CD8 + Treg cells results in increased disease severity and delayed recovery. These data suggest that depletion or inactivation of CD8 + Treg cells represents a potentially effective strategy to enhance protective immunity to chronic viral infection.T-cell exhaustion | killer cell Ig-like receptor | immune regulation

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“…There are at least 27 members that are geographically, serologically, and phylogenetically divided into Old World and New World arenaviruses (1). The prototypic lymphocytic choriomeningitis virus (LCMV) infection of mice has long been used as a valuable model with which to study viral persistence and virus-induced immunity and immunopathology (2,3). The arenavirus is composed of a total of four genes on two genomic RNA segments in opposite orientations (1).…”

mentioning

confidence: 99%

A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose

Dhanwani

Zhou

Huang

et al. 2016

J Virol

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Pichinde virus (PICV) is a bisegmented enveloped RNA virus that targets macrophages and dendritic cells (DCs) early in infection and induces strong innate and adaptive immunity in mice. We have developed a reverse genetics system to produce live recombinant PICV (strain P18) with a trisegmented RNA genome (rP18tri), which encodes all four PICV gene products and as many as two foreign genes. We have engineered the vector to express the green fluorescent protein (GFP) reporter gene (abbreviated as G in virus designations) and either the hemagglutination (HA [H]) or the nucleoprotein (NP [P]) gene of the influenza A/PR8 virus. The trisegmented viruses rP18tri-G/H and rP18tri-G/P showed slightly reduced growth in vitro and expressed HA and NP, respectively. Mice immunized with rP18tri-G/H were completely protected against lethal influenza virus challenge even 120 days after immunization. These rP18tri-based vectors could efficiently induce both neutralizing antibodies and antigen-specific T cell responses via different immunization routes. Interestingly, the immune responses were significantly increased upon a booster dose and remained at high levels even after three booster doses. In summary, we have developed a novel PICV-based live vaccine vector that can express foreign antigens to induce strong humoral and cell-mediated immunity and is ideal for a primeand-boost vaccination strategy. IMPORTANCE We have developed a novel Pichinde virus (PICV)-based live viral vector, rP18tri, that packages three RNA segments and encodes as many as two foreign genes. Using the influenza virus HA and NP genes as model antigens, we show that this rP18tri vector can induce strong humoral and cellular immunity via different immunization routes and can lead to protection in mice. Interestingly, a booster dose further enhances the immune responses, a feature that distinguishes this from other known live viral vectors. In summary, our study demonstrates a unique feature of this live rP18tri vector to be used as a novel vaccine platform for a prime-and-boost vaccination strategy.A renaviruses are enveloped RNA viruses with a bisegmented genome and mostly use rodents as natural hosts. There are at least 27 members that are geographically, serologically, and phylogenetically divided into Old World and New World arenaviruses (1). The prototypic lymphocytic choriomeningitis virus (LCMV) infection of mice has long been used as a valuable model with which to study viral persistence and virus-induced immunity and immunopathology (2, 3). The arenavirus is composed of a total of four genes on two genomic RNA segments in opposite orientations (1). The Z protein, produced from the large (L) genomic segment, is a small RING domain-containing matrix protein that mediates virus budding, regulates viral RNA synthesis, and mediates host immune suppression (4, 5). The large L protein (ϳ200 kDa), also encoded on the L segment, is the RNA-dependent RNA polymerase (RdRp), which is required for viral RNA synthesis (6). The glycoprotein (GPC), encoded...

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Role of Lymphocytic Choriomeningitis Virus (LCMV) in Understanding Viral Immunology: Past, Present and Future

Cited by 107 publications

References 105 publications

Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

Genetic disruption of CD8 ⁺ Treg activity enhances the immune response to viral infection

A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose

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Role of Lymphocytic Choriomeningitis Virus (LCMV) in Understanding Viral Immunology: Past, Present and Future

Cited by 107 publications

References 105 publications

Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

Antigen exposure shapes the ratio between antigen-specific Tregs and conventional T cells in human peripheral blood

Genetic disruption of CD8 + Treg activity enhances the immune response to viral infection

A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose

Contact Info

Product

Resources

About

Genetic disruption of CD8 ⁺ Treg activity enhances the immune response to viral infection