Reversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade.

Highly differentiated CD8(+) CD28(-) CD27(-) T cells have short telomeres, defective telomerase activity and reduced capacity for proliferation. In addition, these cells express increased levels of inhibitory receptors and display defective Akt(ser(473)) phosphorylation following activation. It is not known whether signalling via programmed death 1 (PD-1) contributes to any of the attenuated differentiation-related functional changes in CD8(+) T cells. To address this we blocked PD-1 signalling during T-cell receptor (TCR) activation using antibodies against PD-1 ligand 1 (PDL1) and PDL2. This resulted in a significant enhancement of Akt(ser(473)) phosphorylation and TCR-induced proliferative activity of highly differentiated CD8(+) CD28(-) CD27(-) T cells. In contrast, the reduced telomerase activity in these cells was not altered by blockade of PDL1/2. We also demonstrate that PD-1 signalling can inhibit the proliferative response in primary human CD8(+) T cells from both young and older humans. These data collectively highlight that some, but not all, functional changes that arise during progressive T-cell differentiation and during ageing are maintained actively by inhibitory receptor signalling.