PD-1 Dynamically Regulates Inflammation and Development of Brain-Resident Memory CD8 T Cells During Persistent Viral Encephalitis

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-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.

Formation and Maintenance of Tissue Resident Memory CD8+ T Cells after Viral Infection

“…There are a number of inhibitory receptors expressed by CD8 T RM that likely serve to keep these cells at bay until bona fide antigen recognition occurs through the TCR. Brain T RM cells express PD1, a receptor associated with T cell exhaustion and inability to activate [53,54]. Blockade of PD-1 ligand in tumor settings greatly enhances T cell elimination of cancer cells [55].…”

IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection

“…Adoptive transfer studies of bT RM and the finding that the Pdcd1 locus of brain CD8 T cells, but not spleen CD8 T cells, was demethylated supports that PD-1 expression is intrinsic to bT RM [38]. Nanostring gene expression analysis of the PD-L1 −/− brain microenvironment suggests that the PD-1:PD-L1 pathway decreases neuroinflammation during MuPyV infection [43], further indicating that PD-1 on bT RM protects against CNS damage. T cells isolated from 26 post-mortem brains from patients who died of non-CNS disease showed that both PD-1 and CTLA-4 are expressed by human brain CD8 T cells, but not CD8 T cells in blood [67].…”

“…A recent study of T cells in human brains also found a 40/60% split of CD103 + /CD103 − CD8 T cells; there, CD103 expression correlated with upregulation of homing markers, but without a difference in localization [67]. Interestingly, in both mice and humans, there appears to be an inverse relationship between PD-1 and CD103 expression by CD8 T RM [43,68]. Thus, CD103 expression is an imperfect T RM marker and may not be involved in CNS localization; moreover, whether PD-1 regulates CD103 expression or possibly fosters survival of CD103 − CD8 T cells remains to be determined.…”

“…Like CD103, PD-1 expression by T RM is tissue-and pathogen-dependent [39]. CD103 is expressed by most T RM in the skin, but by fewer CD8 T RM in the brain [7,36,[40][41][42]; PD-1 (also discussed below) is expressed by most T RM in the brain but is less commonly seen on skin T RM [38,39,43,44]. T EX also express PD-1 as well as multiple inhibitory receptors (e.g., Lag-3, 2B4, TIM-3, and CD160) depending on the severity and duration of persistent infection [26].…”

“…The more practical and clinically relevant implication of these recent data is that TCF-1 hi PD-1 + CXCR5 + CD8 T cells, which are found primarily in the lymph nodes, respond to PD-1/PD-L1 blockade and are considered the precursors to the terminally differentiated non-PD-1/PD-L1 blockade responders [63]. Against infectious pathogens in the brain, the reduced effector function by CD8 T EX may sacrifice efficiency in clearing infection, and tolerate pathogen persistence for the sake of reducing tissue damage [38,43].…”