Novel Lymphocytic Choriomeningitis Virus Strain Sustains Abundant Exhausted Progenitor CD8 T Cells without Systemic Viremia

Lalit K Beura, Milcah C Scott, Mark J Pierson, Vineet Joag, Sathi P Wijeyesinghe, Matthew R. Semler, Clare F Quarnstrom, Kathleen Busman-Sahay, Jacob D. Estes, Sara E Hamilton Hart, Vaiva Vezys, David H. O'Connor, David Masopust

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1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1691-1702
Number of pages12
JournalJournal of Immunology
Volume209
Issue number9
DOIs
StatePublished - Nov 1 2022

Bibliographical note

Funding Information:
This work was supported by Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases Grants 1R01AI146032, 3R01AI084913, and 1R01AI150600 to D.M. L.K.B. is a Searle Scholar and also supported by National Institute of General Medical Sciences Grants 2P20GM109035 and P20GM121298. M.C.S. is supported by National Institute of Allergy and Infectious Diseases Grant 1F31AI152353-01A1.

Publisher Copyright:
Copyright © 2022 by The American Association of Immunologists, Inc.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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