CD4 T cells control development and maintenance of brain-resident CD8 T cells during polyomavirus infection

• Published in: PLoS pathogens Vol. 14; no. 10; p. e1007365
• Main Authors: Mockus, Taryn E, Shwetank, Lauver, Matthew D, Ren, Heather M, Netherby, Colleen S, Salameh, Tarik, Kawasawa, Yuka Imamura, Yue, Feng, Broach, James R, Lukacher, Aron E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2018; Public Library of Science (PLoS)
• Subjects: Animals; Biochemistry; Bioinformatics; Biology and life sciences; Brain; Brain - immunology; Brain - virology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - virology; Cell Differentiation; Cytokines; Demyelinating diseases; Demyelination; Dependence; Depletion; Encephalitis; Female; Gene expression; Homeostasis; Immunologic Memory - immunology; Immunology; Infections; Leukoencephalopathy; Lymphocyte Depletion; Lymphocytes; Lymphocytes T; Maintenance; Male; Medicine and health sciences; Memory cells; Mice; Mice, Inbred C57BL; Microorganisms; Molecular biology; Mucosa; Nervous system; Opportunist infection; Pathogens; Polyomavirus - immunology; Polyomavirus Infections - immunology; Polyomavirus Infections - virology; Precision medicine; Progressive multifocal leukoencephalopathy; Proteins; Research and Analysis Methods; Software; Stomatitis; Supervision; Viral infections; Viruses; West Nile virus; United States > US
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007365

Tissue-resident memory CD8 T (TRM) cells defend against microbial reinfections at mucosal barriers; determinants driving durable TRM cell responses in non-mucosal tissues, which often harbor opportunistic persistent pathogens, are unknown. JC polyomavirus (JCPyV) is a ubiquitous constituent of the human virome. With altered immunological status, JCPyV can cause the oft-fatal brain demyelinating disease progressive multifocal leukoencephalopathy (PML). JCPyV is a human-only pathogen. Using the mouse polyomavirus (MuPyV) encephalitis model, we demonstrate that CD4 T cells regulate development of functional antiviral brain-resident CD8 T cells (bTRM) and renders their maintenance refractory to systemic CD8 T cell depletion. Acquired CD4 T cell deficiency, modeled by delaying systemic CD4 T cell depletion until MuPyV-specific CD8 T cells have infiltrated the brain, impacted the stability of CD8 bTRM, impaired their effector response to reinfection, and rendered their maintenance dependent on circulating CD8 T cells. This dependence of CD8 bTRM differentiation on CD4 T cells was found to extend to encephalitis caused by vesicular stomatitis virus. Together, these findings reveal an intimate association between CD4 T cells and homeostasis of functional bTRM to CNS viral infection.