PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation
Alessandra Petrelli, … , Michal Mokry, Femke van Wijk
Alessandra Petrelli, … , Michal Mokry, Femke van Wijk
Published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4669-4681. https://doi.org/10.1172/JCI96107.
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Research Article Immunology

PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation

Abstract

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.

Authors

Alessandra Petrelli, Gerdien Mijnheer, David P. Hoytema van Konijnenburg, Maria M. van der Wal, Barbara Giovannone, Enric Mocholi, Nadia Vazirpanah, Jasper C. Broen, Dirkjan Hijnen, Bas Oldenburg, Paul J. Coffer, Sebastian J. Vastert, Berent J. Prakken, Eric Spierings, Aridaman Pandit, Michal Mokry, Femke van Wijk

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Figure 2

PD1-expressing CD8+ T cells are effector, metabolically active, and not exhausted cells at the target site of inflammatory arthritis.

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PD1-expressing CD8+ T cells are effector, metabolically active, and not ...
(A) Enrichment of previously published gene signatures of CD8+ T cell exhaustion (described in ref. 18) was tested on PD-1+ vs. PD-1–CD8+ T cells from SF by GSEA. (B) Enrichment of previously published gene signatures of effector CD8+ T cells (described in ref. 19) was tested on PD-1+ vs. PD-1–CD8+ T cells from SF by GSEA. NES, normalized enrichment score. (C) Enrichment of genes linked to cell cycle (obtained from the KEGG database) was tested on PD-1+ vs. PD-1–CD8+ T cells from SF. (D) Assessment of cell proliferation was performed by Ki-67 staining on PD-1+ and PD-1–CD8+ T cells from SF-JIA and PB-JIA as well as PB of healthy donors (n = 5 per group). Data are shown as mean ± SD. *P < 0.05, paired Student’s t test. (E) The metabolic phenotype of PD-1+ and PD-1–CD8+ T cells from SF was tested by XF technology (Seahorse Bioscience). Glycolysis was calculated as the difference between levels of ECAR upon exposure to glucose vs. exposure to the glycolysis inhibitor 2-DG. NS, paired Student’s t test. (F) The frequency of IFN-γ–producing (left panel) and TNF-α–producing (right panel) PD-1+ and PD-1–CD8+ T cells was tested upon in vitro PMA/ionomycin stimulation. **P < 0.01, paired Student’s t test. (G) The cytotoxic potential of PD-1+ and PD-1–CD8+ T cells was tested by assessing the frequency of GzmB-producing cells ex vivo (left panel) and upon in vitro PMA/ionomycin stimulation (right panel). **P < 0.01, paired Student’s t test. (H) PD-1–CD8+ T cells were sorted from SF-JIA and plated in the presence of anti-CD3/CD28 stimuli (1:5 ratio). After 40-hour stimulation, intracellular levels of IFN-γ (left panel) and GzmB (right panel) on PD-1+ and PD-1–CD8+ T cells were measured. **P < 0.01, paired Student’s t test SF-PD1+, SF-derived PD1+CD8+ T cells; SF-PD1–, SF-derived PD1–CD8+ T cells; DOWN: downregulated.