Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion
Name
eabd2710.full.pdf
Description
Published version
Size
36.13 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Zhu, Chen
Dixon, Karen O
Newcomer, Kathleen
Gu, Guangxiang
Xiao, Sheng
Zaghouani, Sarah
Schramm, Markus A
Wang, Chao
Zhang, Huiyuan
Goto, Kouichiro
Date Issued
2021
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Version
Final published version
Abstract
T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell-mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3 -/- T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Ludwig Center for Molecular Oncology (Massachusetts Institute of Technology)
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
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DOI of Published Version
https://doi.org/10.1126/sciadv.abd2710
