Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 10, Pages 4669-4681Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI96107
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Funding
- 7th Framework Programme of the EU, SP3-People, Support for Training and Career Development for Researchers (Marie Curie), Network for Initial Training (ITN), FP7-PEOPLE-2011-ITN, under Marie Sklodowska-Curie grant [289903]
- VIDI grant from the Netherlands Organization for Scientific Research (NWO, ZonMW) [91714332]
- Dutch Arthritis Foundation Reumafonds [12-2-404]
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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.
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