PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation
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
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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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 4

PD1-expressing CD8+ T cells are a unique subset undergoing local clonal expansion at the target site of inflammatory arthritis.

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PD1-expressing CD8+ T cells are a unique subset undergoing local clonal ...
Next-generation TCRBV CDR3 sequencing was performed on PD-1+ and PD-1–CD8+ T cells from SF. (A) Simpson’s reciprocal index was assessed as indicator of TCR diversity (left panel). *P < 0.05, paired Student’s t test. Representative pie charts show the distribution of unique clones. (B) Analysis of the clonal proportion showing prevalence of the top clones in PD-1+ and PD-1–CD8+ T cell subsets from SF. (C) Usage of the TCR-Vβ chain was assessed in both PD-1+ and PD-1–CD8+ T cells from SF. (D) Numbers of unique clones and sequences overlapping between PD-1+ and PD-1–CD8+ T cells are shown for patients 1 through 4 by Venn diagrams. (E) Expression of the surrogate marker of antigen specificity TNFRSF9 (i.e., CD137) was assessed in PD-1+ and PD-1–CD8+ T cells from SF both at mRNA (left panel) and protein (right panel) levels. *P < 0.05; **P < 0.01, paired Student’s t test. (F) Telomere length was tested on PD-1+ and PD-1–CD8+ T cells from SF. *P < 0.05, paired Student’s t test. (G) In 1 patient, PD-1+ and PD-1–CD8+ T cells from 2 joints were sorted and TCR sequencing was performed. The number of clones shared between PD-1+ and PD-1–CD8+ T cells coming from the 2 joints are indicated in each square. R, right; L, left.