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J Hepatol. 2018 Sep;69(3):654-665. doi: 10.1016/j.jhep.2018.05.007. Epub 2018 May 18.

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

Author information

1
Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
2
Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
3
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia; Skolkovo Institute of Science and Technology, Moscow, Russia.
4
Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom.
5
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, Moscow, Russia; Skolkovo Institute of Science and Technology, Moscow, Russia; Central European Institute of Technology, Masaryk University, Brno, Czech Republic; Pirogov Russian National Research Medical University, Moscow, Russia.
6
Centre for Liver Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology & Immunotherapy, University of Birmingham, United Kingdom; University Hospital of Birmingham NHS Foundation Trust, United Kingdom. Electronic address: y.h.oo@bham.ac.uk.
7
Cancer Immunology and Immunotherapy Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. Electronic address: b.willcox@bham.ac.uk.

Abstract

BACKGROUND & AIMS:

γδ T cells comprise a substantial proportion of tissue-associated lymphocytes. However, our current understanding of human γδ 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 γδ T cells in the human liver.

METHODS:

We characterised the TCR repertoire, immunophenotype and function of human liver infiltrating γδ T cells, by TCR sequencing analysis, flow cytometry, in situ hybridisation and immunohistochemistry. We focussed on the predominant tissue-associated Vδ2- γδ subset, which is implicated in liver immunopathology.

RESULTS:

Intrahepatic Vδ2- γδ T cells were highly clonally focussed, with single expanded clonotypes featuring complex, private TCR rearrangements frequently dominating the compartment. Such T cells were predominantly CD27lo/- effector lymphocytes, whereas naïve CD27hi, TCR-diverse populations present in matched blood were generally absent in the liver. Furthermore, while a CD45RAhi Vδ2- γδ effector subset present in both liver and peripheral blood contained overlapping TCR clonotypes, the liver Vδ2- γδ T cell pool also included a phenotypically distinct CD45RAlo 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 Vδ2- γδ 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 Vδ2- γδ 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 γδ T cell subsets. They also highlight the inherent functional plasticity within the Vδ2- γδ 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:

γδ 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 γδ T cells are enriched for clonally expanded effector T cells, whereas naïve γδ 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 γδ T cells was also evident. Our findings suggest that factors triggering γδ T cell clonal selection and differentiation, such as infection, can drive enrichment of γδ T cells into liver tissue, allowing the development of functionally distinct tissue-restricted memory populations specialised in local hepatic immunosurveillance.

KEYWORDS:

Gamma delta T cells; Human liver; Immunological memory; Liver immune surveillance; Liver-resident T cells; T cell receptor

PMID:
29758330
PMCID:
PMC6089840
DOI:
10.1016/j.jhep.2018.05.007
[Indexed for MEDLINE]
Free PMC Article

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