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Human intrahepatic CD69?+?CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.

ABSTRACT: Tissue resident memory T cells (T_RM) have been identified in various tissues, however human liver T_RM to date remain unidentified. T_RM can be recognized by CD69 and/or CD103 expression and may play a role in the pathology of chronic hepatitis B (CHB) and hepatitis C virus infection (CHC). Liver and paired blood mononuclear cells from 17 patients (including 4 CHB and 6 CHC patients) were isolated and CD8+ T cells were comprehensively analysed by flowcytometry, immunohistochemistry and qPCR. The majority of intrahepatic CD8+ T cells expressed CD69, a marker used to identify T_RM, of which a subset co-expressed CD103. CD69?+?CD8+ T cells expressed low levels of S1PR1 and KLF2 and a large proportion (>90%) was CXCR6+, resembling liver T_RM in mice and liver resident NK cells in human. Cytotoxic proteins were only expressed in a small fraction of liver CD69?+?CD8+ T cells in patients without viral hepatitis, however, in livers from CHB patients more CD69?+?CD8+ T cells were granzyme B+. In CHC patients, less intrahepatic CD69?+?CD8+ T cells were Hobit+ as compared to CHB and control patients. Intrahepatic CD69?+?CD8+ T cells likely T_RM which have a reduced cytolytic potential. In patients with chronic viral hepatitis T_RM have a distinct phenotype.

SUBMITTER: Stelma F

PROVIDER: S-EPMC5522381 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.

Stelma Femke F de Niet Annikki A Sinnige Marjan J MJ van Dort Karel A KA van Gisbergen Klaas P J M KPJM Verheij Joanne J van Leeuwen Ester M M EMM Kootstra Neeltje A NA Reesink Hendrik W HW

Scientific reports 20170721 1

Tissue resident memory T cells (TRM) have been identified in various tissues, however human liver TRM to date remain unidentified. TRM can be recognized by CD69 and/or CD103 expression and may play a role in the pathology of chronic hepatitis B (CHB) and hepatitis C virus infection (CHC). Liver and paired blood mononuclear cells from 17 patients (including 4 CHB and 6 CHC patients) were isolated and CD8+ T cells were comprehensively analysed by flowcytometry, imm ...[more]

PMID: 28733665

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Project description:ObjectiveGenetic 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.MethodsPeripheral 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).ResultsIL-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.ConclusionOur 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.

Dataset Information

Human intrahepatic CD69?+?CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.

Publications

Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.

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