Repetitive antigen stimulation in the periphery dictates the composition and recall responses of brain-resident memory CD8+ T cells
Madison R. Mix,
Stephanie van de Wall,
Mohammad Heidarian,
Elizabeth A. Escue,
Cori E. Fain,
Lecia L. Pewe,
Lisa S. Hancox,
Sahaana A. Arumugam,
Cassie M. Sievers,
Vladimir P. Badovinac,
John T. Harty
Affiliations
Madison R. Mix
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Stephanie van de Wall
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Mohammad Heidarian
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Experimental Pathology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Elizabeth A. Escue
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Experimental Pathology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Cori E. Fain
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Lecia L. Pewe
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Lisa S. Hancox
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Sahaana A. Arumugam
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Cassie M. Sievers
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Vladimir P. Badovinac
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Experimental Pathology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
John T. Harty
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Experimental Pathology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Corresponding author
Summary: The human brain harbors virus-specific, tissue-resident memory (TRM) CD8+ T cells. However, the impact of repeated peripheral viral infection on the generation, phenotype, localization, and recall responses of brain TRM remains elusive. Here, utilizing two murine models of peripheral viral infection, we demonstrate that circulating memory CD8+ T cells with previous antigen exposure exhibit a markedly reduced capacity to form brain TRM compared to naive CD8+ T cells. Repetitively stimulated brain TRM also demonstrate differential inhibitory receptor expression, preserved functionality, and divergent localization patterns compared to primary memory counterparts. Despite these differences, repetitively stimulated brain TRM provide similar protection against intracranial infection as primary populations with superior recall-based recruitment of peripheral lymphocytes. As CD8+ T cells may distinctly seed the brain with each repeated infection of the same host, these findings point to heterogeneity in the brain TRM pool that is dictated by prior peripheral antigen stimulation history.
