scholarly journals Characterization of CD8 T Cell-Mediated Mutations in the Immunodominant Epitope GP33-41 of Lymphocytic Choriomeningitis Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Mark Smyth ◽  
Kseniya Khamina ◽  
Alexandra Popa ◽  
Venugopal Gudipati ◽  
Benedikt Agerer ◽  
...  
Keyword(s):  
T Cell ◽  
Selection Pressure ◽  
Low Frequency ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Genetically Engineered ◽  
Infection Model ◽  
Chronic Infections ◽  
Synonymous Mutations ◽  
Ctl Escape

Cytotoxic T lymphocytes (CTLs) represent key immune effectors of the host response against chronic viruses, due to their cytotoxic response to virus-infected cells. In response to this selection pressure, viruses may accumulate escape mutations that evade CTL-mediated control. To study the emergence of CTL escape mutations, we employed the murine chronic infection model of lymphocytic choriomeningitis virus (LCMV). We developed an amplicon-based next-generation sequencing pipeline to detect low frequency mutations in the viral genome and identified non-synonymous mutations in the immunodominant LCMV CTL epitope, GP33-41, in infected wildtype mice. Infected Rag2-deficient mice lacking CTLs did not contain such viral mutations. By using transgenic mice with T cell receptors specific to GP33-41, we characterized the emergence of viral mutations in this epitope under varying selection pressure. We investigated the two most abundant viral mutations by employing reverse genetically engineered viral mutants encoding the respective mutations. These experiments provided evidence that these mutations prevent activation and expansion of epitope-specific CD8 T cells. Our findings on the mutational dynamics of CTL escape mutations in a widely-studied viral infection model contributes to our understanding of how chronic viruses interact with their host and evade the immune response. This may guide the development of future treatments and vaccines against chronic infections.

scholarly journals Immune Exhaustion: Past Lessons and New Insights from Lymphocytic Choriomeningitis Virus

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 156 ◽  
Author(s):  
Shannon Kahan ◽  
Allan Zajac
Keyword(s):  
T Cells ◽  
T Cell ◽  
Experimental System ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Exhaustion ◽  
Chronic Infections ◽  
Cell Exhaustion ◽  
Adult Mice ◽  
Track Record

Lymphocytic choriomeningitis virus (LCMV) is a paradigm-forming experimental system with a remarkable track record of contributing to the discovery of many of the fundamental concepts of modern immunology. The ability of LCMV to establish a chronic infection in immunocompetent adult mice was instrumental for identifying T cell exhaustion and this system has been invaluable for uncovering the complexity, regulators, and consequences of this state. These findings have been directly relevant for understanding why ineffective T cell responses commonly arise during many chronic infections including HIV and HCV, as well as during tumor outgrowth. The principal feature of exhausted T cells is the inability to elaborate the array of effector functions necessary to contain the underlying infection or tumor. Using LCMV to determine how to prevent and reverse T cell exhaustion has highlighted the potential of checkpoint blockade therapies, most notably PD-1 inhibition strategies, for improving cellular immunity under conditions of antigen persistence. Here, we discuss the discovery, properties, and regulators of exhausted T cells and highlight how LCMV has been at the forefront of advancing our understanding of these ineffective responses.

scholarly journals The Nucleoprotein Is Required for Lymphocytic Choriomeningitis Virus-Based Vaccine Vector Immunogenicity

2015 ◽  
Vol 89 (22) ◽  
pp. 11734-11738 ◽  
Author(s):  
Stephanie Darbre ◽  
Susan Johnson ◽  
Sandra Kallert ◽  
Paul-Henri Lambert ◽  
Claire-Anne Siegrist ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Viral Transcription ◽  
Genome Replication ◽  
Recombinant Glycoprotein ◽  
Cell Responses ◽  
Deficient Vector

Recombinant glycoprotein-deficient lymphocytic choriomeningitis virus-based vaccine vectors (rLCMV/ΔGP) are potent CD8+T cell inducers. To investigate the underlying molecular requirements, we generated a nucleoprotein-deficient vector counterpart (rLCMV/ΔNP). NP but not GP is a minimaltrans-acting factor for viral transcription and genome replication. We found that, unlike rLCMV/ΔGP, rLCMV/ΔNP failed to elicit detectable CD8+T cell responses unless NP wastranscomplemented in a transgenic host. Hence, NP-dependent intracellular gene expression is essential for LCMV vector immunogenicity.

scholarly journals Immunopathological Basis of Lymphocytic Choriomeningitis Virus-Induced Chorioretinitis and Keratitis

2008 ◽  
Vol 83 (1) ◽  
pp. 159-166 ◽  
Author(s):  
Martin S. Zinkernagel ◽  
Beatrice Bolinger ◽  
Philippe Krebs ◽  
Lucas Onder ◽  
Simone Miller ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Time Course ◽  
Immunosuppressive Agents ◽  
Passive Immunization ◽  
Central Nervous System Disease ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Ocular Disease ◽  
Mouse Strains

ABSTRACT The infection of humans with the rodent-borne lymphocytic choriomeningitis virus (LCMV) can lead to central nervous system disease in adults or severe neurological disease with hydrocephalus and chorioretinitis in children infected congenitally. Although LCMV-induced meningitis and encephalitis have been studied extensively, the immunopathological mechanisms underlying LCMV infection-associated ocular disease remain elusive. We report here that the intraocular administration of the neurotropic LCMV strain Armstrong (Arm) elicited pronounced chorioretinitis and keratitis and that infection with the more viscerotropic strains WE and Docile precipitated less severe immunopathological ocular disease. Time course analyses revealed that LCMV Arm infection of the uvea and neuroretina led to monophasic chorioretinitis which peaked between days 7 and 12 after infection. Analyses of T-cell-deficient mouse strains showed that LCMV-mediated ocular disease was strictly dependent on the presence of virus-specific CD8+ T cells and that the contribution of CD4+ T cells was negligible. Whereas the topical application of immunosuppressive agents did not prevent the development of chorioretinitis, passive immunization with hyperimmune sera partially prevented retinal and corneal damage. Likewise, mice displaying preexisting LCMV-specific T-cell responses were protected against LCMV-induced ocular disease. Thus, antibody- and/or T-cell-based vaccination protocols could be employed as preventive strategies against LCMV-mediated chorioretinitis.

scholarly journals Susceptibility to lymphocytic choriomeningitis virus isolates correlates directly with early and high cytotoxic T cell activity, as well as with footpad swelling reaction, and all three are regulated by H-2D.

1985 ◽  
Vol 162 (6) ◽  
pp. 2125-2141 ◽  
Author(s):  
R M Zinkernagel ◽  
T Leist ◽  
H Hengartner ◽  
A Althage
Keyword(s):  
T Cell ◽  
Virus Isolate ◽  
Cell Activity ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Cytotoxic T Cell ◽  
Mouse Strains ◽  
Time To Death ◽  
Virus Isolates ◽  
Susceptibility Patterns

The lymphocytic choriomeningitis virus (LCMV) isolates Docile (D) and Aggressive (A) of Pfau et al. were studied in various strains of mice. Disease susceptibility, assessed as mortality and time to death to LCMV-D or -A varied greatly amongst mouse strains, and all four possible susceptibility patterns were observed: susceptibility to both (e.g. SWR/J), resistance to both (e.g. DBA/2), susceptibility to A but resistance to D (C57BL/6), or vice versa (CBA/J). Irrespective of the virus isolate or the mouse strain tested, susceptibility correlated with both early and high cytotoxic T cell activity found in spleens or leptomeningeal infiltrates, and with early and high primary footpad swelling reaction after local infection. C57BL/6 mice infected with A or SWR/J infected with A or with D showed, in both test systems, early and high activities; in contrast, DBA/2 mice infected with either D or A, and C57BL/6 infected with D showed no or only slow and low responses in both tests. Early and high LCMV-specific cytotoxic T cell activity, and the rapidity and extent of the primary footpad reaction directly correlated with susceptibility to LCM and all were dominantly regulated by H-2D.

Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 4928-4938 ◽  
Author(s):  
Patricia Ribeiro-dos-Santos ◽  
Emma L. Turnbull ◽  
Marta Monteiro ◽  
Agnès Legrand ◽  
Karen Conrod ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Cell Functions ◽  
Chronic Hiv Infection

Abstract CD8 T cells lose the capacity to control HIV infection, but the extent of the impairment of CD8 T-cell functions and the mechanisms that underlie it remain controversial. Here we report an extensive ex vivo analysis of HIV-specific CD8 T cells, covering the expression of 16 different molecules involved in CD8 function or differentiation. This approach gave remarkably homogeneous readouts in different donors and showed that CD8 dysfunction in chronic HIV infection was much more severe than described previously: some Ifng transcription was observed, but most cells lost the expression of all cytolytic molecules and Eomesodermin and T-bet by chronic infection. These results reveal a cellular mechanism explaining the dysfunction of CD8 T cells during chronic HIV infection, as CD8 T cells are known to maintain some functionality when either of these transcription factors is present, but to lose all cytotoxic activity when both are not expressed. Surprisingly, they also show that chronic HIV and lymphocytic choriomeningitis virus infections have a very different impact on fundamental T-cell functions, “exhausted” lymphocytic choriomeningitis virus-specific cells losing the capacity to secrete IFN-γ but maintaining some cytotoxic activity as granzyme B and FasL are overexpressed and, while down-regulating T-bet, up-regulating Eomesodermin expression.

scholarly journals Lymphocytic Choriomeningitis Virus Infection Yields Overlapping CD4+ and CD8+ T-Cell Responses

2008 ◽  
Vol 82 (23) ◽  
pp. 11734-11741 ◽  
Author(s):  
Courtney Dow ◽  
Carla Oseroff ◽  
Bjoern Peters ◽  
Courtney Nance-Sotelo ◽  
John Sidney ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intracellular Cytokine Staining ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Epitopes ◽  
Binding Assays ◽  
Cell Responses ◽  
Lymphocytic Choriomeningitis Virus Infection

ABSTRACT Activation of CD4+ T cells helps establish and sustain other immune responses. We have previously shown that responses against a broad set of nine CD4+ T-cell epitopes were present in the setting of lymphocytic choriomeningitis virus (LCMV) Armstrong infection in the context of H-2d. This is quite disparate to the H-2b setting, where only two epitopes have been identified. We were interested in determining whether a broad set of responses was unique to H-2d or whether additional CD4+ T-cell epitopes could be identified in the setting of the H-2b background. To pursue this question, we infected C57BL/6 mice with LCMV Armstrong and determined the repertoire of CD4+ T-cell responses using overlapping 15-mer peptides corresponding to the LCMV Armstrong sequence. We confirmed positive responses by intracellular cytokine staining and major histocompatibility complex (MHC)-peptide binding assays. A broad repertoire of responses was identified, consisting of six epitopes. These epitopes originate from the nucleoprotein (NP) and glycoprotein (GP). Out of the six newly identified CD4+ epitopes, four of them also stimulate CD8+ T cells in a statistically significant manner. Furthermore, we assessed these CD4+ T-cell responses during the memory phase of LCMV Armstrong infection and after infection with a chronic strain of LCMV and determined that a subset of the responses could be detected under these different conditions. This is the first example of a broad repertoire of shared epitopes between CD4+ and CD8+ T cells in the context of viral infection. These findings demonstrate that immunodominance is a complex phenomenon in the context of helper responses.

scholarly journals Identification of Db- and Kb-Restricted Subdominant Cytotoxic T-Cell Responses in Lymphocytic Choriomeningitis Virus-Infected Mice

Virology ◽  
1998 ◽  
Vol 240 (1) ◽  
pp. 158-167 ◽  
Author(s):  
Robbert G. van der Most ◽  
Kaja Murali-Krishna ◽  
J.Lindsay Whitton ◽  
Carla Oseroff ◽  
Jeff Alexander ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses
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