Dataset Information

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.

SUBMITTER: Petrelli A

PROVIDER: S-EPMC6159979 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Petrelli Alessandra A Mijnheer Gerdien G Hoytema van Konijnenburg David P DP van der Wal Maria M MM Giovannone Barbara B Mocholi Enric E Vazirpanah Nadia N Broen Jasper C JC Hijnen Dirkjan D Oldenburg Bas B Coffer Paul J PJ Vastert Sebastian J SJ Prakken Berent J BJ Spierings Eric E Pandit Aridaman A Mokry Michal M van Wijk Femke F

The Journal of clinical investigation 20180802 10

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 mo ...[more]

PMID: 30198907

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Project description:Cancer cells frequently undergo chromosome missegregation events during mitosis, whereby the copies of a given chromosome are not distributed evenly among the two daughter cells, thus creating cells with heterogeneous karyotypes. A stochastic model tracing cellular karyotypes derived from clonal populations over hundreds of generations was recently developed and experimentally validated, and it was capable of predicting favorable karyotypes frequently observed in cancer. Here, we construct and study a Markov chain that precisely describes karyotypic evolution during clonally expanding cancer cell populations. The Markov chain allows us to directly predict the distribution of karyotypes and the expected size of the tumor after many cell divisions without resorting to computationally expensive simulations. We determine the limiting karyotype distribution of an evolving tumor population, and quantify its dependency on several key parameters including the initial karyotype of the founder cell, the rate of whole chromosome missegregation, and chromosome-specific cell viability. Using this model, we confirm the existence of an optimal rate of chromosome missegregation probabilities that maximizes karyotypic heterogeneity, while minimizing the occurrence of nullisomy. Interestingly, karyotypic heterogeneity is significantly more dependent on chromosome missegregation probabilities rather than the number of cell divisions, so that maximal heterogeneity can be reached rapidly (within a few hundred generations of cell division) at chromosome missegregation rates commonly observed in cancer cell lines. Conversely, at low missegregation rates, heterogeneity is constrained even after thousands of cell division events. This leads us to conclude that chromosome copy number heterogeneity is primarily constrained by chromosome missegregation rates and the risk for nullisomy and less so by the age of the tumor. This model enables direct integration of karyotype information into existing models of tumor evolution based on somatic mutations.

Dataset Information

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

Publications

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

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