| First Author | Chauhan P | Year | 2021 |
| Journal | Glia | Volume | 69 |
| Issue | 4 | Pages | 858-871 |
| PubMed ID | 33128485 | Mgi Jnum | J:303647 |
| Mgi Id | MGI:6509548 | Doi | 10.1002/glia.23932 |
| Citation | Chauhan P, et al. (2021) Programmed death ligand-1 induction restrains the cytotoxic T lymphocyte response against microglia. Glia 69(4):858-871 |
| abstractText | 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 alpha-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 alpha-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-gamma and IL-2 production when treated with alpha-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. |
