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 October 1, 2018; First published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4669-4681. https://doi.org/10.1172/JCI96107.
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Categories: 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 1

PD1-expressing CD8+ T cells are highly activated at the target site of inflammatory arthritis.

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PD1-expressing CD8+ T cells are highly activated at the target site of i...
(A) PD-1 expression on CD8+ T cells is shown at the site of inflammation of JIA patients (i.e., the SF), PB-JIA, PB-Ch, and PB-HC. Representative dot plots are shown in the left panel. Data are shown as mean ± SD. ***P < 0.0001, 1-way ANOVA. (B) CD45RO expression on PD-1+ and PD-1–CD8+ T cells in indicated samples. Data are shown as mean ± SD. **P < 0.01, paired Student’s t test. (C) PD-1+ and PD-1–CD8+ T cell differentiation is shown by using CD45RA and CCR7 markers. Data are shown as mean from 6 SF-JIA samples. (D) PD-1+ and PD-1–CD8+ T cells were sorted from SF-JIA and PB-HC. Clustering of SF vs. PB PD-1+ and PD-1–CD8+ T cells by PCA is shown. (E) Differentially expressed genes (red dots) between PD-1+ and PD-1–CD8+ T cells in SF and PB are depicted in MA plots. (F) K-means analysis identifies a set of genes specifically upregulated in PD-1+CD8+ T cells from SF. (G) Pathways specifically enriched in PD-1+CD8+ T cells from SF are listed. rec, receptors; polariz., polarization; med., mediated. (H) The heatmap shows color-coded gene expression levels of negative costimulatory markers typically upregulated in exhausted CD8+ T cells in PD-1+ and PD-1–CD8+ T cells from SF. UP, upregulated; N, naive (CD45RA+CCR7+); CM, (CD45RA–CCR7+); EM, effector memory (CD45RA–CCR7–); Ttemra, (CD45RA+CCR7–).