| Autor: |
Shwetank; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States., Frost EL; Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, GA, United States., Mockus TE; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States., Ren HM; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States., Toprak M; Section of Neuropathology, Yale School of Medicine, New Haven, CT, United States., Lauver MD; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States., Netherby-Winslow CS; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States., Jin G; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States., Cosby JM; Department of Pathology, Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Evavold BD; Department of Pathology, Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States., Lukacher AE; Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, United States. |
| Abstrakt: |
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-1 hi , tissue-resident memory population in the brains (bT RM ) 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 bT RM 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. |
