PD-1 dynamically regulates inflammation and development of brain-resident memory CD8 T cells during persistent viral encephalitis

Shwetank, Elizabeth L. Frost, Taryn E. Mockus, Heather M. Ren, Mesut Toprak, Matthew D. Lauver, Colleen S. Netherby-Winslow, Ge Jin, Jennifer M. Cosby, Brian D. Evavold, Aron E. Lukacher

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Abstract

Programmed cell death-1 (PD-1) receptor signaling dampens the functionality of T cells faced with repetitive antigenic stimulation from chronic infections or tumors. Using intracerebral (i.c.) inoculation with mouse polyomavirus (MuPyV), we have shown that CD8 T cells establish a PD-1hi, tissue-resident memory population in the brains (bTRM) of mice with a low-level persistent infection. In MuPyV encephalitis, PD-L1 was expressed on infiltrating myeloid cells, microglia and astrocytes, but not on oligodendrocytes. Engagement of PD-1 on anti-MuPyV CD8 T cells limited their effector activity. NanoString gene expression analysis showed that neuroinflammation was higher in PD-L1−/− than wild type mice at day 8 post-infection, the peak of the MuPyV-specific CD8 response. During the persistent phase of infection, however, the absence of PD-1 signaling was found to be associated with a lower inflammatory response than in wild type mice. Genetic disruption and intracerebroventricular blockade of PD-1 signaling resulted in an increase in number of MuPyV-specific CD8 bTRM and the fraction of these cells expressing CD103, the αE integrin commonly used to define tissue-resident T cells. However, PD-L1−/− mice persistently infected with MuPyV showed impaired virus control upon i.c. re-infection with MuPyV. Collectively, these data reveal a temporal duality in PD-1-mediated regulation of MuPyV-associated neuroinflammation. PD-1 signaling limited the severity of neuroinflammation during acute infection but sustained a level of inflammation during persistent infection for maintaining control of virus re-infection.

Original languageEnglish (US)
Article number783
JournalFrontiers in immunology
Volume10
Issue numberMAR
DOIs
StatePublished - Jan 1 2019

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Shwetank, Frost, E. L., Mockus, T. E., Ren, H. M., Toprak, M., Lauver, M. D., Netherby-Winslow, C. S., Jin, G., Cosby, J. M., Evavold, B. D., & Lukacher, A. E. (2019). PD-1 dynamically regulates inflammation and development of brain-resident memory CD8 T cells during persistent viral encephalitis. Frontiers in immunology, 10(MAR), [783]. https://doi.org/10.3389/fimmu.2019.00783