Reversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade
Open accessAbstract
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.
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In cells that present characteristics of immune senescence, simultaneous blockade of both p38-MAPK and PD-1 signaling supports their proliferation, both in young and older human beings.
“In these cells that present characteristics of immune senescence (decreased proliferation, lower telomerase activity, and increased presence of DNA damage), the simultaneous blockade of both p38-MAPK and PD-1 signaling supports their proliferation, both in young and in older human beings.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [193]
Secretion of TNF-α in some populations of cells is reduced because of the contemporary arrest of p38-MAPK and PD-1 pathways.
“Secretion of TNF-α in some populations of cells is reduced because of the contemporary arrest of p38-MAPK and PD-1 pathways.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [193]
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- Authors
- Henson, S. M., Macaulay, R., Franzese, O., & Akbar, A. N.
- Affiliations
- University College London (GB)
- University of Rome Tor Vergata (IT)
- Venue
- Immunology
- Publisher
- Wiley
- Published
- 2012-03-02
- Volume
- 135
- Issue
- 4
- Pages
- 355-363
- ISSN
- 0019-2805 (ISSN-L)
- 1365-2567
- PMC
- PMC3372750
- OpenAlex
- W1585793952
- Cited by
- 42
- References
- 55
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 1 · 2019: 6 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/J006750/1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- PD-L1, PD-L2, CD8+ T cells, T cell differentiation, telomerase activity, telomeres, Akt phosphorylation, T cell proliferation, inhibitory receptors, T cell receptor stimulation, immunosenescence
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Cell Differentiation, Humans, Lymphocyte Activation, Phosphorylation, CD28 Antigens, Tumor Necrosis Factor Receptor Superfamily, Member 7, CD8-Positive T-Lymphocytes, Proto-Oncogene Proteins c-akt, Young Adult, Programmed Cell Death 1 Receptor
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