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

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 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.

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells

“…Consistent with this, the frequency of anergic CD73 hi FR4 hi CD4 + T cells in the pancreatic lymph node and CD73 hi FR4 - T cells that were either CD4 + or CD8 + significantly increased after Fc.Mut24 treatment. In CD8 + T cells, a lack of CD28 costimulation during activation leads to CD73 upregulation and the generation of regulatory cells that suppress effector T cell responses through CD73-mediated adenosine production ( 84 ). Similarly, CD4 + T cells activated without CD28 costimulation have elevated levels of the Nt5e gene encoding CD73 ( 85 ), suggesting that CD73 upregulation is a common mechanism of T cell tolerance in the absence of sufficient costimulation.…”

The Immune Regulatory Role of Adenosine in the Tumor Microenvironment

“…The expression level of CD73 on CD8 + T cells is regulated by costimulatory signals initiated by the binding of CD28 on the surface of CD8 + T cells to the B7 molecules on target cells. In the absence of CD28 costimulation, CD73 expression levels on CD8 + T cells are upregulated in the TME in several solid cancers [70].…”