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.
Highlights
The inhibitory receptor Programmed cell death-1 (PD-1) plays a dominant role in T cell exhaustion, a state of progressive loss of T cell function resulting from repetitive antigen stimulation such as in chronic viral disease or tumor development [1]
We examined the expression of PD-1 ligands by microglia, oligodendrocytes, and astrocytes, as well as by infiltrating monocytes in mice acutely infected with mouse polyomavirus (MuPyV) (Supplementary Figure 1)
These data show that resident and infiltrating CNS cell types that express PD-L1 are infected with MuPyV with a positive association between PD-L1 expression and virus infection
Summary
The inhibitory receptor PD-1 plays a dominant role in T cell exhaustion, a state of progressive loss of T cell function resulting from repetitive antigen stimulation such as in chronic viral disease or tumor development [1]. Engagement of PD-1 by its ligands PD-L1 (CD274/B7-H1) or PD-L2 (CD273/B7DC) results in recruitment of SHP-phosphatases proximal to the T cell receptor (TCR). These phosphatases inactivate kinase cascades induced by TCR signaling and thereby inhibit downstream pathways required for cytokine production, proliferation, and cytotoxicity [3, 4]. PD-1 mediated T cell exhaustion is characterized by increased expression of the transcription factors Eomesodermin (Eomes) and B lymphocyte-induced maturation protein-1 (Blimp-1), co-expression of inhibitory receptors PD-1, Tim, and 2B4 and diminished effector function [Interferon (IFN)-γ and degranulation] [2, 10]
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