PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation
Open accessAbstract
Chronic inflammatory diseases are characterized by recurrent inflammatory attacks in the tissues mediated by autoreactive T cells. Identity and functional programming of CD8+ T cells at the target site of inflammation still remain elusive. One key question is whether, in these antigen-rich environments, chronic stimulation leads to CD8+ T cell exhaustion comparable to what is observed in infectious disease contexts. In the synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients, a model of chronic inflammation, an overrepresentation of PD-1+CD8+ T cells was found. Gene expression profiling, gene set enrichment analysis, functional studies, and extracellular flux analysis identified PD-1+CD8+ T cells as metabolically active effectors, with no sign of exhaustion. Furthermore, PD-1+CD8+ T cells were enriched for a tissue-resident memory (Trm) cell transcriptional profile and demonstrated increased clonal expansion compared with the PD-1- counterpart, suggesting antigen-driven expansion of locally adapted cells. Interestingly, this subset was also found increased in target tissues in other human chronic inflammatory diseases. These data indicate that local chronic inflammation drives the induction and expansion of CD8+ T cells endowed with potential detrimental properties. Together, these findings lay the basis for investigation of PD-1-expressing CD8+ T cell targeting strategies in human chronic inflammatory diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In organs other than the heart, TRM cells have been incriminated as key drivers of autoimmune diseases including psoriasis, vitiligo, type 1 diabetes, idiopathic arthritis, Alzheimer disease, and multiple sclerosis.
“Moreover, in other organs than the heart, T RM cells have been incriminated as key drivers of autoimmune diseases including psoriasis, vitiligo, type 1 diabetes, idiopathic arthritis, Alzheimer disease, and multiple sclerosis. 294,302-310”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [307]
The supplied passages contain bibliographic information, and searches for tissue-resident memory cells and the named diseases returned no relevant full-text passage. The only substantive match is labeled Abstract; without an eligible full-text passage, the claim that TRM cells are key drivers across the listed diseases cannot be verified from our copy. (LLM, conf=0.67)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · see citing works
Tissue-resident memory T cells: local specialists in immune defence
Mueller, S. N., & Mackay, L. K. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2015.3 · Cited by 1,006 · see citing works
Human memory T cells: generation, compartmentalization and homeostasis
Farber, D. L., Yudanin, N. A., & Restifo, N. P. (2014) · Nature Reviews Immunology · doi:10.1038/nri3567 · Cited by 897 · see citing works
Bengsch, B., Johnson, A. L., Kurachi, M., Odorizzi, P. M., Pauken, K. E., Attanasio, J., Stelekati, E., McLane, L. M., Paley, M. A., Delgoffe, G. M., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.008 · Cited by 868 · see citing works
Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets
Sathaliyawala, T., Kubota, M., Yudanin, N., Turner, D., Camp, P., Thome, J. J. C., Bickham, K. L., Lerner, H., Goldstein, M., Sykes, M., et al. (2013) · Immunity · doi:10.1016/j.immuni.2012.09.020 · Cited by 848 · see citing works
PD-1 signaling in primary T cells
Riley, J. L. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00767.x · Cited by 778 · see citing works
T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection
McKinney, E. F., Lee, J. C., Jayne, D. R. W., Lyons, P. A., & Smith, K. G. C. (2015) · Nature · doi:10.1038/nature14468 · Cited by 685 · see citing works
Watanabe, R., Gehad, A., Yang, C., Scott, L. L., Teague, J. E., Schlapbach, C., Elco, C. P., Huang, V., Matos, T. R., Kupper, T. S., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.3010302 · Cited by 569 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Arthritis flares mediated by tissue-resident memory T cells in the joint
Chang, M. H., Levescot, A., Nelson-Maney, N., Blaustein, R. B., Winden, K. D., Morris, A., Wactor, A., Balu, S., Grieshaber-Bouyer, R., Wei, K., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109902 · Cited by 115 · see citing works
Inhibitory receptor agonists: the future of autoimmune disease therapeutics?
Grebinoski, S., & Vignali, D. A. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.06.001 · Cited by 58 · see citing works
Autoimmune Myocarditis, Old Dogs and New Tricks.
Won, T., Song, E. J., Kalinoski, H. M., Moslehi, J. J., & Čiháková, D. (2024) · Circulation Research · doi:10.1161/circresaha.124.323816 · Cited by 51 · see citing works
van Gisbergen, K. P. J. M., Zens, K. D., & Münz, C. (2021) · European Journal of Immunology · doi:10.1002/eji.202049062 · Cited by 39 · see citing works
Immunological memory in rheumatic inflammation - a roadblock to tolerance induction
Maschmeyer, P., Chang, H.-D., Cheng, Q., Mashreghi, M.-F., Hiepe, F., Alexander, T., & Radbruch, A. (2021) · Nature Reviews Rheumatology · doi:10.1038/s41584-021-00601-6 · Cited by 40 · see citing works
- Authors
- Petrelli, A., Mijnheer, G., van Konijnenburg, D. P. H., van der Wal, M. M., Giovannone, B., Mocholi, E., Vazirpanah, N., Broen, J. C., Hijnen, D., Oldenburg, B., Coffer, P. J., Vastert, S. J., Prakken, B. J., Spierings, E., Pandit, A., Mokry, M., & van Wijk, F.
- Affiliations
- University Medical Center Utrecht (NL)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-08-02
- Volume
- 128
- Issue
- 10
- Pages
- 4669-4681
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6159979
- OpenAlex
- W2892128713
- Cited by
- 126
- References
- 9
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 16 · 2023: 13 · 2022: 11 · 2021: 31 · 2020: 18 · 2019: 14 · 2018: 1
- FWCI
- 6.88
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- EU (FP7-PEOPLE-2011-ITN, Marie Sk<0142>odowska-Curie grant agreement n. 289903)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- PD-1+CD8+ T cells, chronic inflammation, juvenile idiopathic arthritis, synovial fluid, clonal expansion, tissue-resident memory T cells, T cell exhaustion, T cell metabolism, autoreactive T cells, chronic inflammatory diseases
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Chronic Disease, Female, Humans, Immunologic Memory, Infant, Inflammation, Male, CD8-Positive T-Lymphocytes, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
