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.
Highlights
CD28 is required for T cell activation as well as the generation of CD4+Foxp3+ Treg
CD8+ effector T cells were obtained by stimulation of CD28+/+CD8+ T cells from P14 T cell receptor (TCR) transgenic mice with specific antigenic lymphocytic choriomeningitis virus (LCMV) gp[33,34,35,36,37,38,39,40,41] M2 peptide which recognizes LCMV gp[33] in the context of H-2Db on B16. gp[33] melanoma
Since the percentage of tumor-killing was comparable between pretreatment of P14 CD8+ Teff cells with activated CD28WTCD8+ T cells and control P14 CD8+ Teff cells alone, the cytolytic activity of Teff cells co-cultured with activatedCD28WTCD8+ T cells was superior to Teff cells co-cultured with activated CD28KOCD8+ T cells and did not the result from enhanced tumor-killing by the former
Summary
CD28 is required for T cell activation as well as the generation of CD4+Foxp3+ Treg. It is unclear, how CD28 costimulation affects the development of CD8+ T cell suppressive function. Our results showed that ectonucleotidase CD73 expression on CD8+ T cells is upregulated in the absence of CD28 costimulation. T cell activation requires two signals: T cell receptor (TCR) engagement with peptide/MHC complex sends the first signal and ligation of costimulatory molecules transduces the second one to fully activate T cells[1,2]. TCR engagement, ligation of CD28 molecules results in T cell proliferation, increased IL-2 production, and survival[3,4]. “anergic” T cells can act as specific suppressor cells[7,8], but its underlying mechanism is obscure
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