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Reversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade
Sian M Henson1, Richard Macaulay, Ornella Franzese
1Division of Infection and Immunity, University College London, London, UK. s.henson@ucl.ac.uk
Abstract:
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.
Insights
Blocking programmed death 1 (PD-1) signaling enhances T-cell proliferation and Akt phosphorylation in highly differentiated CD8(+) T cells. However, PD-1 blockade does not affect telomerase activity, indicating specific roles in T-cell aging.
Area of Science:
- Immunology
- Cellular Biology
- Aging Research
Background:
- Highly differentiated CD8(+) T cells (CD28(-) CD27(-)) exhibit shortened telomeres, impaired telomerase activity, and reduced proliferation.
- These cells express more inhibitory receptors and show defective Akt phosphorylation upon activation.
- The role of programmed death 1 (PD-1) signaling in these functional declines is unclear.
Purpose of the Study:
- To investigate the impact of PD-1 signaling on the functional deficits of highly differentiated CD8(+) T cells.
- To determine if blocking PD-1 can restore impaired T-cell proliferation and signaling.
Main Methods:
- Antibodies against PD-1 ligands (PDL1 and PDL2) were used to block PD-1 signaling during T-cell receptor (TCR) activation.
- Assessed Akt(ser(473)) phosphorylation, TCR-induced proliferation, and telomerase activity in CD8(+) T cells.
Main Results:
- Blocking PD-1 signaling significantly enhanced Akt(ser(473)) phosphorylation and TCR-induced proliferation in highly differentiated CD8(+) CD28(-) CD27(-) T cells.
- PD-1 blockade did not restore the reduced telomerase activity in these cells.
- PD-1 signaling was found to inhibit proliferation in primary human CD8(+) T cells from both young and older individuals.
Conclusions:
- Programmed death 1 (PD-1) signaling actively maintains some functional impairments associated with T-cell differentiation and aging, specifically affecting proliferation and Akt signaling.
- The inhibitory effects of PD-1 signaling on T-cell function are distinct from its impact on telomerase activity.
- Targeting PD-1 may offer therapeutic potential for age-related T-cell dysfunction.
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