PD-L1/CD80 interaction differentially regulates CD8+ T cell metabolism, survival and GVHD capacity in the presence or absence of PD-1

Abstract

Abstract Purified alloreactive CD8+ T cells induce no acute GVHD, but the mechanisms remain unknown. PD-L1 interacts with PD-1 and CD80. Here we show that, sorted C57BL/6 donor CD8+ T cells (1.25 ×106) expanded in wild-type MHC-mismatched BALB/c recipients but induced no acute GVHD. In PD-L1−/− recipients, donor CD8+ T cells expanded and induced lethal acute GVHD. PD-1−/−CD8+ T cells induced lethal acute GVHD in wild-type recipients. Blockade of PD-L1/CD80 interactions on days 0 and 2 prevented expansion of wild-type and PD-1−/− CD8+ T cells in wild type recipients and prevented acute GVHD caused by PD-1−/− CD8+ T cells. On the other hand, blockade of PD-L1/CD80 interaction after CD8+ T activation on day 5 caused lethal acute GVHD in wild-type recipients that usually have no acute GVHD. Naïve CD8+ T cells express much higher levels of CD80 than PD-1, whereas activated CD8+ T cells express higher levels of PD-1 than CD80. PD-L1/CD80 interaction augmented glycolysis in naïve WT and PD-1−/− CD8+T cells. This interaction was associated with increased phosphorylation of PLC-γ and activation of the AKT/mTOR pathway in a CD28-dependent manner. This interaction increased mitochondrial numbers and volume and augmented ROS production and apoptosis at the peak of CD8+ T cell activation, such that CD8+T cells did not over-expand to cause GVHD. Conversely, blockade of PD-L1/CD80 after CD8+ T activation in the presence of high PD-1 expression led to increased mitophagy, reduced apoptosis and overexpansion of CD8+ T cells, resulting in lethal GVHD. These results indicate that PD-L1/ CD80 interaction is dependent on PD-1 expression to differentially regulate glycolysis and mitophagy as well as expansion, survival and acute GVHD capacity of alloreactive CD8+ T cells.