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Phenotypic and Functional Analysis of Activated Regulatory T Cells Isolated from Chronic Lymphocytic Choriomeningitis Virus-infected Mice
Published on: June 22, 2016
Novel Lymphocytic Choriomeningitis Virus Strain Sustains Abundant Exhausted Progenitor CD8 T Cells without Systemic
Lalit K Beura1, Milcah C Scott2,3, Mark J Pierson2,4
1Department of Molecular Microbiology and Immunology, Brown University, Providence, RI; lalit_beura@brown.edu masopust@umn.edu.
Abstract:
Lymphocytic choriomeningitis virus (LCMV) is the prototypic arenavirus and a natural mouse pathogen. LCMV-Armstrong, an acutely resolved strain, and LCMV-clone 13, a mutant that establishes chronic infection, have provided contrasting infection models that continue to inform the fundamental biology of T cell differentiation, regulation of exhaustion, and response to checkpoint blockade. In this study, we report the isolation and characterization of LCMV-Minnesota (LCMV-MN), which was naturally transmitted to laboratory mice upon cohousing with pet shop mice and shares 80-95% amino acid homology with previously characterized LCMV strains. Infection of laboratory mice with purified LCMV-MN resulted in viral persistence that was intermediate between LCMV-Armstrong and -clone 13, with widely disseminated viral replication and viremia that was controlled within 15-30 d, unless CD4 T cells were depleted prior to infection. LCMV-MN-responding CD8+ T cells biased differentiation toward the recently described programmed death-1 (PD-1)+CXCR5+Tim-3lo stemlike CD8+ T cell population (also referred to as progenitor exhausted T cells) that effectuates responses to PD-1 blockade checkpoint inhibition, a therapy that rejuvenates responses against chronic infections and cancer. This subset resembled previously characterized PD-1+TCF1+ stemlike CD8+ T cells by transcriptional, phenotypic, and functional assays, yet was atypically abundant. LCMV-MN may provide a tool to better understand the breadth of immune responses in different settings of chronic Ag stimulation as well as the ontogeny of progenitor exhausted T cells and the regulation of responsiveness to PD-1 blockade.
Insights
A new Lymphocytic choriomeningitis virus (LCMV) strain, LCMV-Minnesota, causes intermediate viral persistence and promotes a unique stem-like CD8+ T cell population. This discovery aids understanding of chronic infections and immune checkpoint blockade responses.
Area of Science:
- Virology
- Immunology
- T cell biology
Background:
- Lymphocytic choriomeningitis virus (LCMV) is a key arenavirus model.
- LCMV strains like Armstrong and clone 13 offer insights into T cell differentiation and exhaustion.
- Understanding viral persistence and T cell responses is crucial for treating chronic infections and cancer.
Purpose of the Study:
- To isolate and characterize a novel LCMV strain, LCMV-Minnesota (LCMV-MN).
- To investigate the immune response, particularly CD8+ T cell differentiation, induced by LCMV-MN.
- To explore the potential of LCMV-MN as a model for chronic antigen stimulation and T cell exhaustion.
Main Methods:
- Isolation and purification of LCMV-MN from naturally infected mice.
- Infection of laboratory mice with LCMV-MN to assess viral persistence and dissemination.
- Analysis of CD8+ T cell populations, including phenotype, transcription, and function, using flow cytometry and other assays.
- Comparison of LCMV-MN infection with established LCMV strains (Armstrong and clone 13).
Main Results:
- LCMV-MN infection resulted in intermediate viral persistence and widely disseminated replication.
- Viral control was observed within 15-30 days, but this was dependent on CD4 T cell presence.
- LCMV-MN induced a distinct, atypically abundant population of PD-1+CXCR5+Tim-3lo stem-like CD8+ T cells.
- This T cell subset showed functional and phenotypic similarities to previously described progenitor exhausted T cells.
Conclusions:
- LCMV-MN serves as a valuable model for studying intermediate viral persistence and chronic antigen stimulation.
- The virus uniquely shapes CD8+ T cell differentiation towards a stem-like progenitor exhausted phenotype.
- LCMV-MN can advance research into the ontogeny of progenitor exhausted T cells and their response to PD-1 blockade therapy.
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