Clinically resolved psoriatic lesions contain psoriasis-specific IL-17–producing αβ T cell clones

Matos, Tiago R.; O’Malley, John T.; Lowry, Elizabeth L.; Hamm, David; Kirsch, Ilan R.; Robins, Harlan; Kupper, Thomas S.; Krueger, James G.; Clark, Rachael A.

doi:10.1172/jci93396

Cited by 231 publications

(226 citation statements)

References 24 publications

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“…One reason for the differences observed between the previous studies and our own could be patient disease activity. A previous study investigating the clonality of psoriatic skin-derived CD8+ T cells showed that the TCR repertoire is polyclonal in active disease, while in resolved disease only a few dominant clones persist (28). We obtained SF effusions from joints with active inflammation, which could explain the polyclonal repertoire observed.…”

Section: Discussionmentioning

confidence: 91%

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

Steel

Srenathan

Ridley

et al. 2020

Arthritis & Rheumatology

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Objective Genetic associations imply a role for CD8+ T cells and the interleukin‐23 (IL‐23)/IL‐17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL‐17A+CD8+ (Tc17) T cells are enriched in the synovial fluid (SF) of patients with PsA, and IL‐17A blockade is clinically efficacious in PsA/SpA. This study was undertaken to determine the immunophenotype, molecular profile, and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis. Methods Peripheral blood (PB) and SF mononuclear cells were isolated from patients with PsA or other types of SpA. Cells were phenotypically, transcriptionally, and functionally analyzed by flow cytometry (n = 6–18), T cell receptor β (TCRβ) sequencing (n = 3), RNA‐Seq (n = 3), quantitative reverse transcriptase–polymerase chain reaction (n = 4), and Luminex or enzyme‐linked immunosorbent assay (n = 4–16). Results IL‐17A+CD8+ T cells were predominantly TCRαβ+ and their frequencies were increased in the SF versus the PB of patients with established PsA (P < 0.0001) or other SpA (P = 0.0009). TCRβ sequencing showed that these cells were polyclonal in PsA (median clonality 0.08), while RNA‐Seq and deep immunophenotyping revealed that PsA synovial Tc17 cells had hallmarks of Th17 cells (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue‐resident memory T (Trm) cell signature and secreted a range of proinflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 in PsA SF (P = 0.0005), which may contribute to their retention in the joint. Conclusion Our results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA.

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Section: Discussionmentioning

confidence: 91%

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

Steel

Srenathan

Ridley

et al. 2020

Arthritis & Rheumatology

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“… identified the similar motif in an independent cohort, using a different statistical approach based on the estimation of TCR recombination probability (described in detail in ). Sharing of putatively pathogenic clonotypes was also described in psoriasis . Latorre et al .…”

Section: Clonal Sharingmentioning

confidence: 82%

“…Matos et al . showed the presence of large oligoclonal subpopulations of α/β T‐cells in clinically resolved skin lesions from patients with psoriasis. A large fraction of these T‐cells was able to produce IL‐17A, which is believed to be an important driver of psoriasis pathogenesis.…”

Section: Clone Size Distribution Statisticsmentioning

confidence: 99%

T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity

2019

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Summary B‐cell receptors and T‐cell receptors are the key molecules responsible for specific antigen recognition in adaptive immunity. The huge diversity of immune receptor repertoires constrained their comprehensive studies in the past. More recently, however, high‐throughput sequencing based techniques have revolutionized the field of immune receptor repertoire profiling enabling new insights into the development and function of the adaptive immune system. In this review we describe current methods for immune receptor profiling and software tools used for repertoire reconstruction from raw sequencing data. We also provide examples of how immune repertoire profiling can be used to study adaptive immunity in disease and in the course of organ and bone marrow transplantation.

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“…In this report, however, V γ 9 + V δ 2 + cells were activated to produce cytokines from keratinocytes by the specific antigen, suggesting that recognition of specific antigens may be important for the development of psoriasis. Because Th17 cells94 and ILC3s95 as well as γδ 17 cells91 are also detected in the psoriatic skin, the involvement of autoimmunity and the main source of IL‐17 during the development of psoriasis still remain obscure in humans.…”

Section: γδ17 Cells In Human Inflammatory Diseasesmentioning

confidence: 99%

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

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Clinically resolved psoriatic lesions contain psoriasis-specific IL-17–producing αβ T cell clones

Cited by 231 publications

References 24 publications

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

T‐cell receptor and B‐cell receptor repertoire profiling in adaptive immunity

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

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