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

• Published in: Communications biology Vol. 4; no. 1; pp. 595 - 12
• Main Authors: Lai, Yo-Ping, Kuo, Lu-Cheng, Lin, Been-Ren, Lin, Hung-Ju, Lin, Chih-Yu, Chen, Yi-Ting, Hsiao, Pei-Wen, Chang, Huan-Tsung, Ko, Patrick Chow-In, Chen, Hsiao-Chin, Chang, Hsiang-Yu, Lu, Jean, Ho, Hong-Nerng, Wu-Hsieh, Betty A., Kung, John T., Chen, Shu-Ching
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-05-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/21; 13/31; 5'-Nucleotidase - genetics; 5'-Nucleotidase - metabolism; 631/250/580; 631/67/580; 64/110; 64/60; 82/29; 82/58; Adenosine; Animals; Biology; Biomedical and Life Sciences; Cancer immunotherapy; CD28 antigen; CD28 Antigens - metabolism; CD4 antigen; CD73 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Ectonucleotidase; Foxp3 protein; Immunotherapy; Life Sciences; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Solid tumors; T cell receptors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02119-9

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 CD28
−
CD8
+
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.
Lai et al. report that the immunosuppressive molecule CD73 is negatively regulated by CD28 costimulation during CD8
+
 T cell activation. Their study implicates a lack of CD28 costimulation renders CD8
+
 T cells immunosuppressive and less able to eliminate solid tumors.