期刊
CELL REPORTS
卷 27, 期 11, 页码 3315-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.05.041
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资金
- Centre National de la Recherche Scientifique (CNRS)
- INSERM
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program [787300]
- Agence Nationale de la Recherche (PHENOMIN project)
- MSDAVENIR Fund
- AstraZeneca-MedImmune
- Plan Cancer [C15091AS]
- DC Biol Labex [ANR-11-LABEX-0043, ANR-10-IDEX-0001-02 PSL]
- MSDAVENIR
- China Scholarship Council
- ERC [670821]
- Swiss National Science Foundation [3100A0-688107679]
- Innovative Medicines Initiative project ULTRA-DD [115766]
- European Research Council (ERC) [787300, 670821] Funding Source: European Research Council (ERC)
Deciphering how TCR signals are modulated by coinhibitory receptors is of fundamental and clinical interest. Using quantitative interactomics, we define the composition and dynamics of the PD-1 and BTLA coinhibitory signalosomes in primary effector T cells and at the T cell-antigen-presenting cell interface. We also solve the existing controversy regarding the role of the SHP-1 and SHP-2 protein-tyrosine phosphatases in mediating PD-1 coinhibition. PD-1 predominantly recruits SHP-2, but when absent, it recruits SHP-1 and remains functional. In contrast, BTLA predominantly recruits SHP-1 and to a lesser extent SHP-2. By separately analyzing the PD-1-SHP-1 and PD-1-SHP-2 complexes, we show that both dampen the TCR and CD28 signaling pathways equally. Therefore, our study illustrates how comparison of coinhibitory receptor signaling via quantitative interactomics in primary T cells unveils their extent of redundancy and provides a rationale for designing combinations of blocking antibodies in cancer immunotherapy on the basis of undisputed modes of action.
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