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 Lukacher

Research output: Contribution to journalArticle

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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Viral Encephalitis
Encephalitis
Polyomavirus
Cell Death
T-Lymphocytes
Infection
Programmed Cell Death 1 Receptor
Oligodendroglia
Microglia
Virus Diseases
Myeloid Cells
Infection Control
Integrins
Astrocytes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Shwetank ; Frost, Elizabeth L. ; Mockus, Taryn E. ; Ren, Heather M. ; Toprak, Mesut ; Lauver, Matthew D. ; Netherby-Winslow, Colleen S. ; Jin, Ge ; Cosby, Jennifer M. ; Evavold, Brian D. ; Lukacher, Aron. / PD-1 dynamically regulates inflammation and development of brain-resident memory CD8 T cells during persistent viral encephalitis. In: Frontiers in immunology. 2019 ; Vol. 10, No. MAR.
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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.",
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Shwetank, Frost, EL, Mockus, TE, Ren, HM, Toprak, M, Lauver, MD, Netherby-Winslow, CS, Jin, G, Cosby, JM, Evavold, BD & Lukacher, A 2019, 'PD-1 dynamically regulates inflammation and development of brain-resident memory CD8 T cells during persistent viral encephalitis', Frontiers in immunology, vol. 10, no. MAR, 783. https://doi.org/10.3389/fimmu.2019.00783

PD-1 dynamically regulates inflammation and development of brain-resident memory CD8 T cells during persistent viral encephalitis. / Shwetank; Frost, Elizabeth L.; Mockus, Taryn E.; Ren, Heather M.; Toprak, Mesut; Lauver, Matthew D.; Netherby-Winslow, Colleen S.; Jin, Ge; Cosby, Jennifer M.; Evavold, Brian D.; Lukacher, Aron.

In: Frontiers in immunology, Vol. 10, No. MAR, 783, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Shwetank,

AU - Frost, Elizabeth L.

AU - Mockus, Taryn E.

AU - Ren, Heather M.

AU - Toprak, Mesut

AU - Lauver, Matthew D.

AU - Netherby-Winslow, Colleen S.

AU - Jin, Ge

AU - Cosby, Jennifer M.

AU - Evavold, Brian D.

AU - Lukacher, Aron

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