PUBLICATION
Novel PD-L1/BTLA Checkpoint Axis Exploited for Bacterial Immune Escape by Restraining CD8+ T Cell-Initiated Adaptive Immunity in Zebrafish
- Authors
- Hu, C.B., Huang, C., Wang, J., Hong, Y., Fan, D.D., Chen, Y., Lin, A.F., Xiang, L.X., Shao, J.Z.
- ID
- ZDB-PUB-230725-38
- Date
- 2023
- Source
- Journal of immunology (Baltimore, Md. : 1950) 211(5): 816-835 (Journal)
- Registered Authors
- Fan, Dongdong, Lin, Aifu, Shao, Jian-zhong, Xiang, Lixin
- Keywords
- none
- MeSH Terms
-
- Animals
- B7-H1 Antigen*/metabolism
- CD8-Positive T-Lymphocytes
- Humans
- Mammals
- Programmed Cell Death 1 Receptor/metabolism
- Receptors, Immunologic/metabolism
- Zebrafish*
- PubMed
- 37486225 Full text @ J. Immunol.
Citation
Hu, C.B., Huang, C., Wang, J., Hong, Y., Fan, D.D., Chen, Y., Lin, A.F., Xiang, L.X., Shao, J.Z. (2023) Novel PD-L1/BTLA Checkpoint Axis Exploited for Bacterial Immune Escape by Restraining CD8+ T Cell-Initiated Adaptive Immunity in Zebrafish. Journal of immunology (Baltimore, Md. : 1950). 211(5):816-835.
Abstract
Programmed death-ligand 1/programmed cell death 1 (PD-L1/PD-1) is one of the most important immune checkpoints in humans and other mammalian species. However, the occurrence of the PD-L1/PD-1 checkpoint in evolutionarily ancient vertebrates remains elusive because of the absence of a PD-1 homolog before its appearance in tetrapods. In this article, we identified, to our knowledge, a novel PD-L1/B and T lymphocyte attenuator (BTLA) checkpoint in zebrafish by using an Edwardsiella tarda-induced bacterial infection model. Results showed that zebrafish (Danio rerio) PD-L1 (DrPD-L1) and BTLA (DrBTLA) were differentially upregulated on MHC class II+ macrophages (Mϕs) and CD8+ T cells in response to E. tarda infection. DrPD-L1 has a strong ability to interact with DrBTLA, as shown by the high affinity (KD = 5.68 nM) between DrPD-L1/DrBTLA proteins. Functionally, the breakdown of DrPD-L1/DrBTLA interaction significantly increased the cytotoxicity of CD8+BTLA+ T cells to E. tarda-infected PD-L1+ Mϕ cells and reduced the immune escape of E. tarda from the target Mϕ cells, thereby enhancing the antibacterial immunity of zebrafish against E. tarda infection. Similarly, the engagement of DrPD-L1 by soluble DrBTLA protein diminished the tolerization of CD8+ T cells to E. tarda infection. By contrast, DrBTLA engagement by a soluble DrPD-L1 protein drives aberrant CD8+ T cell responses. These results were finally corroborated in a DrPD-L1-deficient (PD-L1-/-) zebrafish model. This study highlighted a primordial PD-L1/BTLA coinhibitory axis that regulates CD8+ T cell activation in teleost fish and may act as an alternative to the PD-L1/PD-1 axis in mammals. It also revealed a previously unrecognized strategy for E. tarda immune evasion by inducing CD8+ T cell tolerance to target Mϕ cells through eliciting the PD-L1/BTLA checkpoint pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping