CD28 engagement inhibits CD73-mediated regulatory activity of CD8+ T cells

Yo Ping Lai, Lu Cheng Kuo, Been Ren Lin, Hung Ju Lin, Chih Yu Lin, Yi Ting Chen, Pei Wen Hsiao, Huan Tsung Chang, Patrick Chow In Ko, Hsiao Chin Chen, Hsiang Yu Chang, Jean Lu, Hong Nerng Ho, Betty A. Wu-Hsieh, John T. Kung, Shu Ching Chen

Research output: Contribution to journalArticlepeer-review

Abstract

CD28 is required for T cell activation as well as the generation of CD4+Foxp3+ Treg. It is unclear, however, how CD28 costimulation affects the development of CD8+ T cell suppressive function. Here, by use of Hepa1.6.gp33 in vitro killing assay and B16.gp33 tumor mouse model we demonstrate that CD28 engagement during TCR ligation prevents CD8+ T cells from becoming suppressive. Interestingly, our results showed that ectonucleotidase CD73 expression on CD8+ T cells is upregulated in the absence of CD28 costimulation. In both murine and human tumor-bearing hosts, CD73 is upregulated on CD28CD8+ T cells that infiltrate the solid tumor. UPLC-MS/MS analysis revealed that CD8+ T cells activation without CD28 costimulation produces elevated levels of adenosine and that CD73 mediates its production. Adenosine receptor antagonists block CD73-mediated suppression. Our data support the notion that CD28 costimulation inhibits CD73 upregulation and thereby prevents CD8+ T cells from becoming suppressive. This study uncovers a previously unidentified role for CD28 costimulation in CD8+ T cell activation and suggests that the CD28 costimulatory pathway can be a potential target for cancer immunotherapy.

Original languageEnglish
Article number595
JournalCommunications Biology
Volume4
Issue number1
DOIs
Publication statusPublished - Dec 2021

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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