Glial Cell Expression of PD-L1

Chauhan, Priyanka; Lokensgard, James R.

doi:10.3390/ijms20071677

Cited by 35 publications

(31 citation statements)

References 81 publications

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“…We have previously shown that glial cells govern the activity of brain‐infiltrating anti‐viral T‐cells via upregulation of PD‐L1 expression, likely in an effort to mitigate potentially damaging encephalitis (Schachtele, Hu, Sheng, Mutnal, & Lokensgard, 2014). Although these immunosuppressive responses are undeniably beneficial to the host, preventing damage to this vital organ, establishment of a prolonged anti‐inflammatory milieu may also result in deficiencies in viral clearance from infected brain cells (Chauhan & Lokensgard, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Our laboratory has developed an experimental murine model in which the brain becomes populated with long‐lived CD8 + T‐cells specific for immunodominant HIV‐1 Gag epitopes (Prasad, Hu, Sheng, Chauhan & Lokensgard, 2019). High numbers of activated CD8 + T‐cells against HIV antigens in the CSF of acutely infected patients have been reported (Kessing et al, 2017; Schrier et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, we have previously shown that both microglial cells and astrocytes upregulate PD‐L1 upon activation and this PD‐L1 expression negatively regulated cytokine production by activated T‐cells (Schachtele et al, 2014). Furthermore, this negative regulation was partially reversed following α‐PD‐1 or α‐PD‐L1 (but not α‐PD‐L2) treatment (Chauhan & Lokensgard, 2019; Schachtele et al, 2014). The current study expands on our previous work by investigating the role of the PD‐1: PD‐L1 pathway in restraining cytolytic responses of bT RM against HIV‐1 peptide‐presenting microglia.…”

Section: Introductionmentioning

confidence: 99%

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Programmed death ligand‐1 induction restrains the cytotoxic T lymphocyte response against microglia

Chauhan

Prasad

et al. 2020

Glia

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Microglial cells are the main reservoir for HIV‐1 within the brain and potential exists for negative immune checkpoint blockade therapies to purge this viral reservoir. Here, we investigated cytolytic responses of CD8+ T lymphocytes against microglia loaded with peptide epitopes. Initially, flow cytometric analysis demonstrated efficient killing of HIV‐1 p24 AI9 or YI9 peptide‐loaded splenocytes in MHC‐matched recipients. Cytolytic killing of microglia was first demonstrated using ovalbumin (OVA) as a model antigen for in vitro cytotoxic T lymphocyte (CTL) assays. Peptide‐loaded primary microglia obtained from programmed death ligand (PD‐L) 1 knockout (KO) animals showed significantly more killing than cells from wild‐type (WT) animals when co‐cultured with activated CD8+ T‐cells isolated from rAd5‐OVA primed animals. Moreover, when peptide loaded‐microglial cells from WT animals were treated with neutralizing α‐PD‐L1 Ab, significantly more killing was observed compared to either untreated or IgG isotype‐treated cells. Most importantly, significantly increased in vivo killing of HIV‐1 p24 YI9 peptide‐loaded microglia from PD‐L1 KO animals, as well as AI9 peptide‐loaded BALB/c microglial cells treated with α‐PD‐L1, was observed within brains of rAd5‐p24 primed‐CNS boosted C57BL/6 or BALB/c mice, respectively. Finally, ex vivo responses of brain CD8+ T‐cells in response to AI9 stimulation showed significantly increased IFN‐γ and IL‐2 production when treated with α‐PD‐1 Abs. Greater proliferation of CD8+ T‐cells from the brain was also observed following blockade. Taken together, these studies demonstrate that PD‐L1 induction on microglia restrains CTL responses and indicate that immune checkpoint blockade targeting this pathway may be beneficial in clearing viral brain reservoirs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Programmed death ligand‐1 induction restrains the cytotoxic T lymphocyte response against microglia

Chauhan

Prasad

et al. 2020

Glia

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“…During inflammation, PDL1 expression is induced in astrocytes, oligodendrocytes [67] and endothelial cells [68] and upregulated in microglia [12] and neurons. Upregulation or induction of PDL1 in microglia and astrocytes during inflammation may limit CNS inflammation and pathology by inhibition of T cell activation [69]. In EAE, for example, responses of infiltrating PD1-expressing T cells are suppressed by microglia PDL1 expression [70].…”

Section: Immune Checkpoints In the Cnsmentioning

confidence: 99%

Exploring the VISTA of microglia: immune checkpoints in CNS inflammation

et al. 2020

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Negative checkpoint regulators (NCR) are intensely pursued as targets to modulate the immune response in cancer and autoimmunity. A large variety of NCR is expressed by central nervous system (CNS)-resident cell types and is associated with CNS homeostasis, interactions with peripheral immunity and CNS inflammation and disease. Immunotherapy blocking NCR affects the CNS as patients can develop neurological issues including encephalitis and multiple sclerosis (MS). How these treatments affect the CNS is incompletely understood, since expression and function of NCR in the CNS are only beginning to be unravelled. V-type immunoglobulin-like suppressor of T cell activation (VISTA) is an NCR that is expressed primarily in the haematopoietic system by myeloid and T cells. VISTA regulates T cell quiescence and activation and has a variety of functions in myeloid cells including efferocytosis, cytokine response and chemotaxis. In the CNS, VISTA is predominantly expressed by microglia and macrophages of the CNS. In this review, we summarize the role of NCR in the CNS during health and disease. We highlight expression of VISTA across cell types and CNS diseases and discuss the function of VISTA in microglia and during CNS ageing, inflammation and neurodegeneration. Understanding the role of VISTA and other NCR in the CNS is important considering the adverse effects of immunotherapy on the CNS, and in view of their therapeutic potential in CNS disease.

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“…It is well known that microglial cells belong to the monocyte-macrophage system based on their source of occurrence and characteristics, showing antigen presentation function and secretion of a variety of active factors. PD-L1 is identi ed in the glial cells and expressional change is observed under CNS in ammatory state (24,25). However, it is still lack of studies on PD-1/PD-L1 working in the neurodegenerative diseases, especially relation to microglial activation and neuroin ammatory response.…”

Section: Introductionmentioning

confidence: 99%

PD-1 Knockout Aggravates Motor Dysfunction In The MPTP Model of Parkinson's Disease By Inducing Microglial Activation And Neuroinflammation In Mice

Cheng

Chen

Bian

et al. 2021

Preprint

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Background: Abundant microglial reaction and neuroinflammation are typical pathogenetic hallmark of brains in Parkinson’s disease (PD) patients, but regulation mechanisms are poorly understood. In this study, the promoting effects of PD-1-difficiency on microglial activation, neuroinflammation and motor dysfunction were identified using PD animal model.Methods: Using C57 wild-type (WT), PD-1 knockout (KO) and MPTP model, we designed WT-control, KO-control, WT-MPTP and KO-MPTP groups. Motor dysfunction of animal, distribution of PD-1-positive cells, dopaminergic neuronal survival, glial cell activation and generation of inflammatory cytokines in midbrains were observed by behavior detection, immunohistochemistry and western blot methods. Results: Microglial cells showing PD-1/Iba1 double-positivity were numerously distributed in the substantia nigra of control whereas they decreased in MPTP model. Compared with WT-MPTP, KO-MPTP mice exacerbated in their motor dysfunction, decreased level of TH expression and decreased TH-positive neuronal protrusions. Microglial cell activation and expression of proinflammatory cytokine iNOS, TNF-α, IL-1β and IL-6 significantly increased, and levels and phosphorylation of AKT and ERK1/2 were also elevated in KO-MPTP mice. Conclusions: PD-1 knockout could aggravate motor dysfunction of MPTP mouse model by promoting microglial activation and neuroinflammation in midbrains, suggesting that PD-1 signaling abnormality might be involved in PD pathogenesis or progression.

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Glial Cell Expression of PD-L1

Cited by 35 publications

References 81 publications

Programmed death ligand‐1 induction restrains the cytotoxic T lymphocyte response against microglia

Programmed death ligand‐1 induction restrains the cytotoxic T lymphocyte response against microglia

Exploring the VISTA of microglia: immune checkpoints in CNS inflammation

PD-1 Knockout Aggravates Motor Dysfunction In The MPTP Model of Parkinson's Disease By Inducing Microglial Activation And Neuroinflammation In Mice

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