Programmed death ligand‐1 induction restrains the cytotoxic T lymphocyte response against microglia
| Autor: | James R. Lokensgard, Wen S. Sheng, Shuxian Hu, Sujata Prasad, Priyanka Chauhan |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Programmed Cell Death 1 Receptor CD8-Positive T-Lymphocytes Biology B7-H1 Antigen Article Epitope Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Antigen medicine Animals Cytotoxic T cell Immune Checkpoint Inhibitors Mice Inbred BALB C Microglia Molecular biology Immune checkpoint Mice Inbred C57BL CTL 030104 developmental biology medicine.anatomical_structure Neurology Peptides 030217 neurology & neurosurgery Ex vivo CD8 T-Lymphocytes Cytotoxic |
| Zdroj: | Glia |
| ISSN: | 1098-1136 0894-1491 |
| DOI: | 10.1002/glia.23932 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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