Pet shop mice are infected with a novel lymphocytic choriomeningitis virus strain that sustains an abundance of stem-like PD-1+ CD8 T cells

Abstract

Abstract Lymphocytic choriomeningitis virus (LCMV) is a natural mouse pathogen. LCMV Armstrong, an acutely resolved strain, and LCMV Clone13, 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. Here, we describe LCMV Minnesota (LCMV-MN), which was 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 widely disseminated viral replication and viremia that was controlled within 15–30 days; which is of intermediate duration between LCMV Armstrong and Clone13. The magnitude of the LCMV-MN specific CD8+ T cell was maintained at much higher levels than that observed after LCMV Armstrong or Clone13 infections. LCMV-MN responding CD8+ T cells were further associated with significantly biased differentiation towards the recently described PD1+ CXCR5+ Tim-3lo stem-like CD8+ T cell population that was previously shown to be largely responsible for responsiveness to PD-1 inhibitory checkpoint blockade. In contrast to LCMV Clone13-induced responses, this subset persisted after resolution of LCMV-MN viremia, yet transcriptionally, phenotypically and functionally resembled PD1+ TCF1+ stem-like CD8+ T cells maintained by LCMV Clone13 infection. Together with existing models, LCMV-MN may contribute to a better understanding of the breadth of immune response in different chronic infections or tumor settings as well as the regulation of responsiveness to PD-1 blockade.