PMID- 34548339
OWN - NLM
STAT- MEDLINE
DCOM- 20220609
LR  - 20240320
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Print)
IS  - 0017-5749 (Linking)
VI  - 71
IP  - 7
DP  - 2022 Jul
TI  - The human liver microenvironment shapes the homing and function of CD4(+) T-cell 
      populations.
PG  - 1399-1411
LID - 10.1136/gutjnl-2020-323771 [doi]
AB  - OBJECTIVE: Tissue-resident memory T cells (T(RM)) are vital immune sentinels that 
      provide protective immunity. While hepatic CD8(+) T(RM) have been well described, 
      little is known about the location, phenotype and function of CD4(+) T(RM). 
      DESIGN: We used multiparametric flow cytometry, histological assessment and novel 
      human tissue coculture systems to interrogate the ex vivo phenotype, function and 
      generation of the intrahepatic CD4(+) T-cell compartment. We also used leukocytes 
      isolated from human leukocyte antigen (HLA)-disparate liver allografts to assess 
      long-term retention. RESULTS: Hepatic CD4(+) T cells were delineated into three 
      distinct populations based on CD69 expression: CD69(-), CD69(INT) and CD69(HI). 
      CD69(HI)CD4(+) cells were identified as tissue-resident CD4(+) T cells on the 
      basis of their exclusion from the circulation, phenotypical profile 
      (CXCR6(+)CD49a(+)S1PR1(-)PD-1(+)) and long-term persistence within the pool of 
      donor-derived leukcoocytes in HLA-disparate liver allografts. CD69(HI)CD4(+) T 
      cells produced robust type 1 polyfunctional cytokine responses on stimulation. 
      Conversely, CD69(INT)CD4(+) T cells represented a more heterogenous population 
      containing cells with a more activated phenotype, a distinct chemokine receptor 
      profile (CX(3)CR1(+)CXCR3(+)CXCR1(+)) and a bias towards interleukin-4 
      production. While CD69(INT)CD4(+) T cells could be found in the circulation and 
      lymph nodes, these cells also formed part of the long-term resident pool, 
      persisting in HLA-mismatched allografts. Notably, frequencies of CD69(INT)CD4(+) 
      T cells correlated with necroinflammatory scores in chronic hepatitis B 
      infection. Finally, we demonstrated that interaction with hepatic epithelia was 
      sufficient to generate CD69(INT)CD4(+) T cells, while additional signals from the 
      liver microenvironment were required to generate liver-resident CD69(HI)CD4(+) T 
      cells. CONCLUSIONS: High and intermediate CD69 expressions mark human hepatic 
      CD4(+) T(RM) and a novel functionally distinct recirculating population, 
      respectively, both shaped by the liver microenvironment to achieve diverse 
      immunosurveillance.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published 
      by BMJ.
FAU - Wiggins, Benjamin G
AU  - Wiggins BG
AUID- ORCID: 0000-0001-5215-2004
AD  - Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, 
      UK.
AD  - Institute of Immunity and Transplantation, Division of Infection and Immunity, 
      University College London, London, UK.
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK.
FAU - Pallett, Laura J
AU  - Pallett LJ
AUID- ORCID: 0000-0002-4161-9462
AD  - Institute of Immunity and Transplantation, Division of Infection and Immunity, 
      University College London, London, UK.
FAU - Li, Xiaoyan
AU  - Li X
AD  - Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, 
      UK.
AD  - Department of Infectious Diseases and Guangdong Provincial Key Laboratory of 
      Liver Disease Research, Third Affiliated Hospital of Sun Yat-Sen University, 
      Guangzhou, China.
FAU - Davies, Scott P
AU  - Davies SP
AD  - Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, 
      UK.
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK.
FAU - Amin, Oliver E
AU  - Amin OE
AD  - Institute of Immunity and Transplantation, Division of Infection and Immunity, 
      University College London, London, UK.
FAU - Gill, Upkar S
AU  - Gill US
AD  - Immunobiology, Blizard Institute, London, UK.
FAU - Kucykowicz, Stephanie
AU  - Kucykowicz S
AD  - Institute of Immunity and Transplantation, Division of Infection and Immunity, 
      University College London, London, UK.
FAU - Patel, Arzoo M
AU  - Patel AM
AD  - Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, 
      UK.
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK.
FAU - Aliazis, Konstantinos
AU  - Aliazis K
AD  - Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, 
      UK.
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK.
FAU - Liu, Yuxin S
AU  - Liu YS
AD  - Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, 
      UK.
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK.
FAU - Reynolds, Gary M
AU  - Reynolds GM
AD  - Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, 
      UK.
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK.
FAU - Davidson, Brian R
AU  - Davidson BR
AD  - Surgery, Royal Free Campus, UCL Medical School, London, UK.
FAU - Gander, Amir
AU  - Gander A
AD  - Tissue Access for Patient Benefit, University College London, London, UK.
FAU - Luong, Tu Vinh
AU  - Luong TV
AD  - Department of Cellular Pathology, Royal Free Hospital, London, UK.
FAU - Hirschfield, Gideon M
AU  - Hirschfield GM
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK.
AD  - Centre for Liver Research, National Institute for Health Research Biomedical 
      Research Unit, University of Birmingham, Birmingham, UK.
FAU - Kennedy, Patrick T F
AU  - Kennedy PTF
AUID- ORCID: 0000-0001-9201-0094
AD  - Immunobiology, Blizard Institute, London, UK.
FAU - Huang, Yuehua
AU  - Huang Y
AD  - Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen 
      University, Guangzhou, Guangdong, China.
AD  - Guangdong Provincial Key Laboratory of Liver Disease Research, Third Affiliated 
      Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
FAU - Maini, Mala K
AU  - Maini MK
AD  - Division of Infection and Immunity, Rayne Institute, University College London, 
      London, UK z.stamataki@bham.ac.uk m.maini@ucl.ac.uk.
FAU - Stamataki, Zania
AU  - Stamataki Z
AUID- ORCID: 0000-0003-3823-4497
AD  - Centre for Liver and Gastrointestinal Research, University of Birmingham, 
      Birmingham, UK z.stamataki@bham.ac.uk m.maini@ucl.ac.uk.
LA  - eng
GR  - MRF_MRF-044-0004-F-GILL-C0823/MRF/MRF/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - MRF_MRF-044-0005-F-TRIV-C0824/MRF/MRF/United Kingdom
GR  - PB-PG-0614-34087/DH_/Department of Health/United Kingdom
GR  - 107389/Z/15/Z/WT_/Wellcome Trust/United Kingdom
GR  - 26813/CRUK_/Cancer Research UK/United Kingdom
GR  - MRF_MRF-169-0001-F-STAM-C0826/MRF/MRF/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210921
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (Cytokines)
SB  - IM
MH  - *CD4-Positive T-Lymphocytes
MH  - CD8-Positive T-Lymphocytes
MH  - Cytokines/immunology
MH  - Humans
MH  - Immunologic Memory
MH  - *Liver/immunology
MH  - Monitoring, Immunologic
PMC - PMC9185819
OTO - NOTNLM
OT  - T lymphocytes
OT  - cellular immunity
OT  - hepatitis B
OT  - immunology
OT  - liver immunology
COIS- Competing interests: BW collaborated with and received funding from Bioniz. LJP 
      sat on advisory boards/provided consultancy for Gilead Sciences and SQZ Biotech. 
      KA was funded by a studentship with Dr Falk. MKM received research funding from 
      Gilead Sciences, Hoffmann La Roche and Immunocore. MKM sat on advisory 
      boards/provided consultancy for Gilead, Hoffmann La Roche, Immunocore, VIR, 
      Galapagos NV, GSK, Abbvie and Freeline. ZS collaborated with Bioniz and 
      AstraZeneca and consulted for Boehringer Ingelheim. All other authors declare no 
      conflict of interest.
EDAT- 2021/09/23 06:00
MHDA- 2022/06/10 06:00
PMCR- 2022/06/10
CRDT- 2021/09/22 06:14
PHST- 2020/12/09 00:00 [received]
PHST- 2021/08/19 00:00 [accepted]
PHST- 2021/09/23 06:00 [pubmed]
PHST- 2022/06/10 06:00 [medline]
PHST- 2021/09/22 06:14 [entrez]
PHST- 2022/06/10 00:00 [pmc-release]
AID - gutjnl-2020-323771 [pii]
AID - 10.1136/gutjnl-2020-323771 [doi]
PST - ppublish
SO  - Gut. 2022 Jul;71(7):1399-1411. doi: 10.1136/gutjnl-2020-323771. Epub 2021 Sep 21.