Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 6, Pages 1567-1580Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20162115
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Funding
- Medical Research Council [G0801213]
- Wellcome Trust [101849/Z/13/A]
- Barts and the London School of Medicine and Dentistry
- London Charity [723/1795]
- Medical Research Council [G0801213] Funding Source: researchfish
- National Institute for Health Research [ACF-2009-19-002, 10/4001/11] Funding Source: researchfish
- Wellcome Trust [101849/Z/13/Z] Funding Source: researchfish
- Wellcome Trust [101849/Z/13/A] Funding Source: Wellcome Trust
- MRC [G0801213] Funding Source: UKRI
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The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)-infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-bet(lo)Eomes(lo)Blimp-1(hi)Hobit(lo) T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69(+)CD103(+) CXCR6(+)CXCR3(+)). These tissue-resident memory T cells (T-RM) are preferentially expanded in patients with partial immune control of HBV infection and can remain in the liver after the resolution of infection, including compartmentalized responses against epitopes within all major HBV proteins. Sequential IL-15 or antigen exposure followed by TGFa induces liver-adapted T-RM, including their signature high expression of exhaustion markers PD-1 and CD39. We suggest that these inhibitory molecules, together with paradoxically robust, rapid, cell-autonomous IL-2 and IFN gamma production, equip liver CD8 T-RM to survive while exerting local noncytolytic hepatic immunosurveillance.
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