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Human liver infiltrating gamma delta T cells are composed of clonally expanded circulating and tissue-resident populations

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F18%3A00106637" target="_blank" >RIV/00216224:14740/18:00106637 - isvavai.cz</a>

  • Výsledek na webu

    <a href="http://dx.doi.org/10.1016/j.jhep.2018.05.007" target="_blank" >http://dx.doi.org/10.1016/j.jhep.2018.05.007</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1016/j.jhep.2018.05.007" target="_blank" >10.1016/j.jhep.2018.05.007</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Human liver infiltrating gamma delta T cells are composed of clonally expanded circulating and tissue-resident populations

  • Popis výsledku v původním jazyce

    Background &amp; Aims: gamma delta T cells comprise a substantial proportion of tissue-associated lymphocytes. However, our current understanding of human gamma delta T cells is primarily based on peripheral blood subsets, while the immunobiology of tissue-associated subsets remains largely unclear. Therefore, we aimed to elucidate the T cell receptor (TCR) diversity, immunophenotype and function of gamma delta T cells in the human liver. Methods: We characterised the TCR repertoire, immunophenotype and function of human liver infiltrating gamma delta T cells, by TCR sequencing analysis, flow cytometry, in situ hybridisation and immunohistochemistry. We focussed on the predominant tissue-associated V delta 2(-) gamma delta subset, which is implicated in liver immunopathology. Results: Intrahepatic V delta 2(-) gamma delta T cells were highly clonally focussed, with single expanded clonotypes featuring complex, private TCR rearrangements frequently dominating the compartment. Such T cells were predominantly CD27(lo/-) effector lymphocytes, whereas naive CD27(hi), TCR-diverse populations present in matched blood were generally absent in the liver. Furthermore, while a CD45RA(hi) V delta 2(-) gamma delta effector subset present in both liver and peripheral blood contained overlapping TCR clonotypes, the liver V delta 2(-) gamma delta T cell pool also included a phenotypically distinct CD45RA(lo) effector compartment that was enriched for expression of the tissue tropism marker CD69, the hepatic homing chemokine receptors CXCR3 and CXCR6, and liver-restricted TCR clonotypes, suggestive of intrahepatic tissue residency. Liver infiltrating V delta 2(-) gamma delta cells were capable of polyfunctional cytokine secretion, and unlike peripheral blood subsets, were responsive to both TCR and innate stimuli. Conclusion: These findings suggest that the ability of V delta 2(-) gamma delta T cells to undergo clonotypic expansion and differentiation is crucial in permitting access to solid tissues, such as the liver, which results in functionally distinct peripheral and liver-resident memory gamma delta T cell subsets. They also highlight the inherent functional plasticity within the V delta 2(-) gamma delta T cell compartment and provide information that could be used for the design of cellular therapies that suppress liver inflammation or combat liver cancer. Lay summary: gamma delta T cells are frequently enriched in many solid tissues, however the immunobiology of such tissue-associated subsets in humans has remained unclear. We show that intrahepatic gamma delta T cells are enriched for clonally expanded effector T cells, whereas naive gamma delta T cells are largely excluded. Moreover, whereas a distinct proportion of circulating T cell clonotypes was present in both the liver tissue and peripheral blood, a functionally and clonotypically distinct population of liver-resident gamma delta T cells was also evident. Our findings suggest that factors triggering gamma delta T cell clonal selection and differentiation, such as infection, can drive enrichment of gamma delta T cells into liver tissue, allowing the development of functionally distinct tissue-restricted memory populations specialised in local hepatic immunosurveillance. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V.

  • Název v anglickém jazyce

    Human liver infiltrating gamma delta T cells are composed of clonally expanded circulating and tissue-resident populations

  • Popis výsledku anglicky

    Background &amp; Aims: gamma delta T cells comprise a substantial proportion of tissue-associated lymphocytes. However, our current understanding of human gamma delta T cells is primarily based on peripheral blood subsets, while the immunobiology of tissue-associated subsets remains largely unclear. Therefore, we aimed to elucidate the T cell receptor (TCR) diversity, immunophenotype and function of gamma delta T cells in the human liver. Methods: We characterised the TCR repertoire, immunophenotype and function of human liver infiltrating gamma delta T cells, by TCR sequencing analysis, flow cytometry, in situ hybridisation and immunohistochemistry. We focussed on the predominant tissue-associated V delta 2(-) gamma delta subset, which is implicated in liver immunopathology. Results: Intrahepatic V delta 2(-) gamma delta T cells were highly clonally focussed, with single expanded clonotypes featuring complex, private TCR rearrangements frequently dominating the compartment. Such T cells were predominantly CD27(lo/-) effector lymphocytes, whereas naive CD27(hi), TCR-diverse populations present in matched blood were generally absent in the liver. Furthermore, while a CD45RA(hi) V delta 2(-) gamma delta effector subset present in both liver and peripheral blood contained overlapping TCR clonotypes, the liver V delta 2(-) gamma delta T cell pool also included a phenotypically distinct CD45RA(lo) effector compartment that was enriched for expression of the tissue tropism marker CD69, the hepatic homing chemokine receptors CXCR3 and CXCR6, and liver-restricted TCR clonotypes, suggestive of intrahepatic tissue residency. Liver infiltrating V delta 2(-) gamma delta cells were capable of polyfunctional cytokine secretion, and unlike peripheral blood subsets, were responsive to both TCR and innate stimuli. Conclusion: These findings suggest that the ability of V delta 2(-) gamma delta T cells to undergo clonotypic expansion and differentiation is crucial in permitting access to solid tissues, such as the liver, which results in functionally distinct peripheral and liver-resident memory gamma delta T cell subsets. They also highlight the inherent functional plasticity within the V delta 2(-) gamma delta T cell compartment and provide information that could be used for the design of cellular therapies that suppress liver inflammation or combat liver cancer. Lay summary: gamma delta T cells are frequently enriched in many solid tissues, however the immunobiology of such tissue-associated subsets in humans has remained unclear. We show that intrahepatic gamma delta T cells are enriched for clonally expanded effector T cells, whereas naive gamma delta T cells are largely excluded. Moreover, whereas a distinct proportion of circulating T cell clonotypes was present in both the liver tissue and peripheral blood, a functionally and clonotypically distinct population of liver-resident gamma delta T cells was also evident. Our findings suggest that factors triggering gamma delta T cell clonal selection and differentiation, such as infection, can drive enrichment of gamma delta T cells into liver tissue, allowing the development of functionally distinct tissue-restricted memory populations specialised in local hepatic immunosurveillance. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    30102 - Immunology

Návaznosti výsledku

  • Projekt

    <a href="/cs/project/LQ1601" target="_blank" >LQ1601: CEITEC 2020</a><br>

  • Návaznosti

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Ostatní

  • Rok uplatnění

    2018

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Journal of Hepatology

  • ISSN

    0168-8278

  • e-ISSN

  • Svazek periodika

    69

  • Číslo periodika v rámci svazku

    3

  • Stát vydavatele periodika

    NL - Nizozemsko

  • Počet stran výsledku

    12

  • Strana od-do

    654-665

  • Kód UT WoS článku

    000441734200015

  • EID výsledku v databázi Scopus

    2-s2.0-85049327635