Liver-resident CD8+ T cells: Learning lessons from the local experts

Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic liversJournal of HepatologyVol. 72Issue 6PreviewHuman liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. Full-Text PDF See Article, pages 1170–1181 See Article, pages 1170–1181 Recent studies in humans as well as animal models have highlighted the importance of CD8+ memory T cells compartmentalised at the site of disease, known as tissue-resident memory T cells (CD8+ TRM). These local immune sentinels are highly adapted to maintain functionality within tissues, providing efficient in situ immunity at hotspots for pathogen encounter. They can provide continual immunosurveillance and pathogen control through the rapid production of critical mediators such as IFNγ.[1]Masopust D. Soerens A.G. Tissue-resident T cells and other resident leukocytes.Annu Rev Immunol. 2019; 37: 521-546Crossref PubMed Scopus (275) Google Scholar Conversely, CD8+ TRM have been linked with tissue-specific damage and autoimmunity.[2]Sasson S.C. Gordon C.L. Christo S.N. Klenerman P. Mackay L.K. Local heroes or villains: tissue-resident memory T cells in human health and disease.Cell Mol Immunol. 2020; 17: 113-122Crossref PubMed Scopus (36) Google Scholar It is clear that TRM in general can be considered "friend," whilst maintaining successful immune control, or "foe", when contributing to immunopathology or autoimmunity. But what is known about CD8+ TRM in the human liver? Tissue-resident CD8+ T cells (including HBV-specific responses) have previously been identified in the human liver, with increased frequencies associated with better control of HBV infection.3Stelma F. De Niet A. Sinnige M.J. Van Dort K.A. Van Gisbergen K.P.J.M. Verheij J. et al.Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.Sci Rep. 2017; 7: 6172Crossref PubMed Scopus (67) Google Scholar, 4Gill U.S. Pallett L.J. Thomas N. Burton A.R. Patel A.A. Yona S. et al.Fine needle aspirates comprehensively sample intrahepatic immunity.Gut. 2019; 68: 1493-1503Crossref PubMed Scopus (46) Google Scholar, 5Wong M.T. Ong D.E.H. Lim F.S.H. Teng K.W.W. McGovern N. Narayanan S. et al.A high-dimensional atlas of human T cell diversity reveals tissue-specific trafficking and cytokine signatures.Immunity. 2016; 45: 442-456Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 6Pallett L.J. Davies J. Colbeck E.J. Robertson F. Hansi N. Easom N.J.W. et al.IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J Exp Med. 2017; 214: 1567-1580Crossref PubMed Scopus (207) Google Scholar However, more than 2 decades ago, evidence emerged supporting a dual role for CD8+ T cells in the HBV-infected liver, with HBV-specific CD8+ T cells that failed to control viral replication exacerbating progressive organ damage via the recruitment of bystander non-antigen-specific cells.7Maini M.K. Boni C. Lee C.K. Larrubia J.R. Reignat S. Ogg G.S. et al.The role of virus-specific CD8+ cells in liver damage and viral control during persistent hepatitis B virus infection.J Exp Med. 2000; 191: 1269-1280Crossref PubMed Scopus (678) Google Scholar, 8Bertoletti A. Maini M.K. Protection or damage: a dual role for the virus-specific cytotoxic T lymphocyte response in hepatitis B and C infection?.Curr Opin Immunol. 2000; 3: 387-392Google Scholar, 9Ando K. Moriyama T. Guidotti L.G. Wirth S. Schreiber R.D. Schlicht H.J. et al.Mechanisms of class I restricted immunopathology. A tramgenic mouse model of fulminant hepatitis.J Exp Med. 1993; 178: 1541-1554Crossref PubMed Scopus (417) Google Scholar This concept was elegantly extended in a recent publication by Kim et al. showing that bystander liver damage in viral hepatitis can be mediated by innate-like cytolytic activity of CD8+ T cells.[10]Kim J. Chang D.Y. Lee H.W. Lee H. Kim J.H. Sung P.S. et al.Innate-like cytotoxic function of bystander-activated CD8 + T cells is associated with liver injury in acute hepatitis A.Immunity. 2018; 48: 161-173.e5Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar In this issue of Journal of Hepatology, Kim et al. accessed large number of perfusates from living liver donors to investigate the heterogeneity within the CD8+ TRM compartment to further unpick their roles in immunity and pathology.[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google Scholar Their data suggest that a subset of those liver CD8+ T cells that are capable of contributing to bystander liver damage can be regulated by hypoxia-inducible factor (HIF)-2α. Two markers consistently associated with CD8+ TRM are the tissue retention molecules; CD69 (S1PR1 antagonist, preventing tissue egress) and CD103 (integrin αE that binds E-cadherin[3]Stelma F. De Niet A. Sinnige M.J. Van Dort K.A. Van Gisbergen K.P.J.M. Verheij J. et al.Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.Sci Rep. 2017; 7: 6172Crossref PubMed Scopus (67) Google Scholar,[6]Pallett L.J. Davies J. Colbeck E.J. Robertson F. Hansi N. Easom N.J.W. et al.IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J Exp Med. 2017; 214: 1567-1580Crossref PubMed Scopus (207) Google Scholar); however, phenotypic and functional diversity that is yet to be decoded exists within TRM subsets defined using these markers alone[1]Masopust D. Soerens A.G. Tissue-resident T cells and other resident leukocytes.Annu Rev Immunol. 2019; 37: 521-546Crossref PubMed Scopus (275) Google Scholar,[2]Sasson S.C. Gordon C.L. Christo S.N. Klenerman P. Mackay L.K. Local heroes or villains: tissue-resident memory T cells in human health and disease.Cell Mol Immunol. 2020; 17: 113-122Crossref PubMed Scopus (36) Google Scholar,[12]Steinert E.M. Schenkel J.M. Fraser K.A. Beura L.K. Manlove L.S. Igyarto B.Z. et al.Quantifying memory CD8 T cells reveals regionalization of immunosurveillance.Cell. 2015; 161: 737-749Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar (Table 1). The human liver houses sizeable populations of both CD69+CD103- and CD69+CD103+ CD8+ T cells, that can be separated from infiltrating, but non-resident, CD69-CD103- T cells by their expression of several features common to resident memory T cells (S1PR1hi, CXCR6, CD49a and a lack of KLF2 expression).1Masopust D. Soerens A.G. Tissue-resident T cells and other resident leukocytes.Annu Rev Immunol. 2019; 37: 521-546Crossref PubMed Scopus (275) Google Scholar, 2Sasson S.C. Gordon C.L. Christo S.N. Klenerman P. Mackay L.K. Local heroes or villains: tissue-resident memory T cells in human health and disease.Cell Mol Immunol. 2020; 17: 113-122Crossref PubMed Scopus (36) Google Scholar, 3Stelma F. De Niet A. Sinnige M.J. Van Dort K.A. Van Gisbergen K.P.J.M. Verheij J. et al.Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.Sci Rep. 2017; 7: 6172Crossref PubMed Scopus (67) Google Scholar,[6]Pallett L.J. Davies J. Colbeck E.J. Robertson F. Hansi N. Easom N.J.W. et al.IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J Exp Med. 2017; 214: 1567-1580Crossref PubMed Scopus (207) Google Scholar,[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google Scholar Kim et al. specifically highlight the numerical dominance of the CD69+CD103- TRM-like population, that express chemokine receptors supporting liver retention (CXCR6, CXCR3, and a lack of CX3CR1[1]Masopust D. Soerens A.G. Tissue-resident T cells and other resident leukocytes.Annu Rev Immunol. 2019; 37: 521-546Crossref PubMed Scopus (275) Google Scholar,[3]Stelma F. De Niet A. Sinnige M.J. Van Dort K.A. Van Gisbergen K.P.J.M. Verheij J. et al.Human intrahepatic CD69 + CD8+ T cells have a tissue resident memory T cell phenotype with reduced cytolytic capacity.Sci Rep. 2017; 7: 6172Crossref PubMed Scopus (67) Google Scholar,[6]Pallett L.J. Davies J. Colbeck E.J. Robertson F. Hansi N. Easom N.J.W. et al.IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J Exp Med. 2017; 214: 1567-1580Crossref PubMed Scopus (207) Google Scholar,[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google Scholar) but exhibit an intermediate phenotype between the non-resident, tissue-infiltrating CD69-CD103- and CD69+CD103+ TRM. Prolonged exposure to environmental cues may be needed for a CD69+CD103- TRM-like cell to differentiate into a double positive CD69+CD103+ TRM; cytokines, such as TGFβ and IL-33, are known inducers of CD103 expression.[6]Pallett L.J. Davies J. Colbeck E.J. Robertson F. Hansi N. Easom N.J.W. et al.IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J Exp Med. 2017; 214: 1567-1580Crossref PubMed Scopus (207) Google Scholar,[13]Mackay L.K. Wynne-Jones E. Freestone D. Pellicci D.G. Mielke L.A. Newman D.M. et al.T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate.Immunity. 2015; 43: 1101-1111Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar TCR engagement by cognate antigen recognition within the tissue may also drive CD103 expression:[6]Pallett L.J. Davies J. Colbeck E.J. Robertson F. Hansi N. Easom N.J.W. et al.IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J Exp Med. 2017; 214: 1567-1580Crossref PubMed Scopus (207) Google Scholar,[14]Khan T.N. Mooster J.L. Kilgore A.M. Osborn J.F. Nolz J.C. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection.J Exp Med. 2016; 213: 951-966Crossref PubMed Scopus (137) Google Scholar in support of this, Kim et al. find more CD103 expression on intrahepatic T cells specific for hepatotropic compared to non-hepatotropic viral infections.[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google ScholarTable 1Comparison of human blood and liver-resident CD8+ T cell populations.Marker (gene name)Blood non-TEMRABlood TEMRACD69− CD103− Liver infiltratingCD69+ CD103− TRM-likeCD69+ CD103+ TRMFrequency in the livern.an.a++++/++++/++Tissue retention CD69+∗CD69 expression on a small number of CD8+ T cells in the blood has been attributed to recent activation.+∗CD69 expression on a small number of CD8+ T cells in the blood has been attributed to recent activation.-+++++ CD103 (ITGAE)----++ CXCR3---+++++ CXCR6---++++ CD49a (ITGA1)??-+++ CX3CR1+++-- S1PR1+++?+++-- LFA-1 (ITGAL)++++++++Transcription factors Blimp1 (PRDM1)---+++++ Hobit (ZNF683)++?++-- Tbet (TBX21)++++++++++ Eomesodermin (EOMES)+++++++++ TCF1++-??? KLF2++++++-- HIF2α+?++++Innate-like function/senescence NKG2D-++-++++ CD57 (B3GAT1)-+++++++ KLRG-1-+++-++-Differentiation/specificity CD45RA+ CCR7+, naïve+++-+-- CD45RA− CCR7+, TCM+---- CD45RA− CCR7− , TEM++-+++++++ CD45RA+ CCR7− , TEMRAˆCD45RA+ are excluded from analysis of TRM subsets in some publications.-+++-++/- PD-1 (PDCD1)++++++++++ HBV-specific (hepatotropic virus)+++++++ CMV-specific (non-hepatotropic virus)+++++++++-CMV, cytomegalovirus; TCM, central memory T cells; TEM, effector memory T cells, TEMRA, terminally differentiated effector memory; TRM, tissue-resident memory T cell.The relative protein expression (from minimal - to highest +++) of indicated markers for each T cell subset.∗ CD69 expression on a small number of CD8+ T cells in the blood has been attributed to recent activation.ˆ CD45RA+ are excluded from analysis of TRM subsets in some publications. Open table in a new tab CMV, cytomegalovirus; TCM, central memory T cells; TEM, effector memory T cells, TEMRA, terminally differentiated effector memory; TRM, tissue-resident memory T cell. The relative protein expression (from minimal - to highest +++) of indicated markers for each T cell subset. The CD69+CD103- TRM-like population described by Kim et al. are enriched for terminally differentiated memory T cells expressing CD45RA (TEMRA; CD45RA re-expression, CCR7-), which are also readily identified in the blood, and expand with age and cytomegalovirus (CMV) seropositivity.[15]Akbar A.N. Henson S.M. Lanna A. Senescence of T Lymphocytes: implications for enhancing human immunity.Trends Immunol. 2016; 37: 866-876Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar Despite their name, TEMRA are far from inert or fully senescent T cells as they have the ability to mediate pathogen clearance and/or tissue damage via innate-like cytotoxic pathways, such as NKG2D.[14]Khan T.N. Mooster J.L. Kilgore A.M. Osborn J.F. Nolz J.C. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection.J Exp Med. 2016; 213: 951-966Crossref PubMed Scopus (137) Google Scholar Interestingly, Kim et al. show that CD69+CD103- TRM-like cells responded to stimulation with the prototypical liver cytokine IL-15 by upregulating NKG2D, which also conferred on them innate-like cytolytic function, in line with the authors' recent study.[10]Kim J. Chang D.Y. Lee H.W. Lee H. Kim J.H. Sung P.S. et al.Innate-like cytotoxic function of bystander-activated CD8 + T cells is associated with liver injury in acute hepatitis A.Immunity. 2018; 48: 161-173.e5Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar,[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google Scholar Whilst IL-15-driven expansion of heterologous CD8+ T cell responses may contribute to protection in acute viral infections,[16]Sandalova E. Laccabue D. Boni C. Tan A.T. Fink K. Ooi E.E. et al.Contribution of herpesvirus specific CD8 T cells to anti-viral T cell response in humans.PLoS Pathog. 2010; 6: e1001051Crossref PubMed Scopus (58) Google Scholar in situations of chronic inflammation it can represent a tissue-specific danger signal, that promotes damage through licensing of bystander T cells and NK cells.[17]Jabri B. Abadie V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction.Nat Rev Immunol. 2015; 15: 771-783Crossref PubMed Scopus (180) Google Scholar The highly abundant CD69+CD103- TRM-like population could, therefore, represent a pool of T cells lodged within the local microenvironment with the potential to mediate cytotoxic bystander tissue damage. The liver has regions that are hypoxic, attributable to its dominant venous blood supply and sluggish sinusoidal blood flow.[18]Carreau A. El Hafny-Rahbi B. Matejuk A. Grillon C. Kieda C. Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia.J Cell Mol Med. 2011; 15: 1239-1253Crossref PubMed Scopus (758) Google Scholar T cells can sense the local oxygen gradient and adjust their gene expression by stabilising the transcription factors HIF1α and HIF2α.[19]Doedens A.L. Phan A.T. Stradner M.H. Fujimoto J.K. Nguyen J.V. Yang E. et al.Hypoxia-inducible factors enhance the effector responses of CD8 + T cells to persistent antigen.Nat Immunol. 2013; 14: 1173-1182Crossref PubMed Scopus (403) Google Scholar Thus, the expression of HIF2α by CD69+CD103- TRM-like cells suggests they may be located in particularly hypoxic regions, although this remains to be investigated. Using pharmacological or genetic knockdown of HIF2α, Kim et al. show that this transcription factor is required by CD69+CD103- T cells for survival and optimal functionality upon bystander or TCR-stimulation.[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google Scholar Although HIF1α expression has been linked to T cell differentiation and metabolic reprogramming,[20]Phan A.T. Goldrath A.W. Hypoxia-inducible factors regulate T cell metabolism and function.Mol Immunol. 2015; 68: 527-535Crossref PubMed Scopus (50) Google Scholar the role of HIF2α has not been studied in detailed. CD69+CD103- T cells were the dominant population in livers with acute hepatitis A infection or cirrhosis, and their expression of HIF2α was further increased in disease.[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google Scholar Potential links between hypoxia and HIF-dependent T cell functionality, and their roles as biomarkers and drivers of liver pathology require further study. HIF2α was uniquely enriched within intrahepatic CD69+CD103- T cells compared to TRM from other human tissues such as, lung, colon and kidney. It is unsurprising that T cells manifest organ-specific adaptations considering that each site is anatomically distinct and encounters different environmental and microbial insults. For example, T cells can respond to arginine starvation by increasing nutrient transporters for the uptake of alternative amino acids (marked by CD98[21]Pallett L.J. Gill U.S. Quaglia A. Sinclair L.V. Jover-Cobos M. Schurich A. et al.Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells.Nat Med. 2015; 21: 591-600Crossref PubMed Scopus (185) Google Scholar), an adaptation noted on human liver-resident T cells.[6]Pallett L.J. Davies J. Colbeck E.J. Robertson F. Hansi N. Easom N.J.W. et al.IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection.J Exp Med. 2017; 214: 1567-1580Crossref PubMed Scopus (207) Google Scholar Another adaptation recently discovered in human T cells that reside in the hostile, hypoxic liver environment is an increase in basal autophagy levels, a process that can remove the depolarised mitochondria that limit metabolic flexibility of exhausted T cells, as well as providing biomolecules for cellular metabolism.[22]Swadling L. Pallett L.J. Diniz M.O. Baker J.M. Amin O.E. Stegmann K.A. et al.Human liver memory CD8+ T cells use autophagy for tissue residence.Cell Rep. 2020; 30: 687-698.e6Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Conversely, murine liver TRM are enriched for the purinergic receptor P2RX7, allowing them to be selectively depleted by ischemia and other causes of sterile tissue damage such as acetaminophen poisoning.[23]Stark R. Wesselink T.H. Behr F.M. Kragten N.A.M. Arens R. Koch-Nolte F. et al.TRM maintenance is regulated by tissue damage via P2RX7.Sci Immunol. 2018; 3Crossref PubMed Scopus (80) Google Scholar Future research efforts should aim to address the many unresolved questions regarding the functionality of heterogenous TRM subsets in the liver, to pave the way for the development of novel vaccines and immunotherapies tackling the global health priorities targeting the liver, including hepatitis B and C infection, malaria, and hepatocellular carcinoma. A pressing issue to address is the in situ localisation of TRM subsets and their relevant interactions with the underlying parenchyma and other cell types. The liver has a complex structure with distinct anatomic regions where different cellular, soluble, and stromal mediators could influence T cell migration and function, which cannot be adequately assessed with traditional methods for dissociating bulk tissues for single cell analysis. High resolution in situ multiparameter imaging of well-preserved tissue sections will further reveal functional and phenotypic differences dependent on topological features, whilst the state-of-the-art technique NICHE-seq, combining photoactivatable reporters and singe-cell RNA-sequencing,[24]Medaglia C. Giladi A. Stoler-Barak L. De Giovanni M. Salame T.M. Biram A. et al.Spatial reconstruction of immune niches by combining photoactivatable reporters and scRNA-seq.Science. 2017; 358: 1622-1626Crossref PubMed Scopus (126) Google Scholar could allow detailed spatial reconstruction of the liver-resident T cell niche. The existence of bona fide resident populations mediating hepatic immunosurveillance has been shown for murine CD8+ T cells by parabiosis experiments and intravital imaging of their intrasinsoidal patrolling;[12]Steinert E.M. Schenkel J.M. Fraser K.A. Beura L.K. Manlove L.S. Igyarto B.Z. et al.Quantifying memory CD8 T cells reveals regionalization of immunosurveillance.Cell. 2015; 161: 737-749Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar their localisation within the liver sinusoidal vasculature is compatible with the observation, in this and previous studies, that TRM can be isolated from liver perfusates. Whilst CD69+CD103+ T cells are not observed in the blood, the intrahepatic CD69+CD103- T cell fraction (the focus of Kim et al.'s study) has partially overlapping features with some circulating populations (summarised in Table 1). Thus, additional phenotypic and/or transcriptional markers that can better distinguish the full complement of subsets that are exclusively liver-resident are still needed. In addition, further studies confirming the longevity and retention of CD8+ T cells with a TRM phenotype in the human liver would support their therapeutic potential in providing sustained local immunosurveillance. Such immunosurveillance may extend to primary and secondary liver tumours, since emerging data support a critical role for CD8+ TRM in the immune control of tumours.[25]Amsen D. Van Gisbergen K.P.J.M. Hombrink P. Van Lier R.A.W. Tissue-resident memory T cells at the center of immunity to solid tumors.Nat Immunol. 2018; 19: 538-546Crossref PubMed Scopus (150) Google Scholar The capacity of liver TRM to sense and drive tissue damage should also stimulate studies of their role in regulating liver inflammation and fibrosis in disease settings like non-alcoholic steatohepatitis. The novel finding by Kim et al. of HIF2α-dependent intrahepatic T cells underscores the value of sampling liver-resident immune populations in studies of pathological tissues and therapeutic interventions (whether by biopsy or fine needle aspiration[4]Gill U.S. Pallett L.J. Thomas N. Burton A.R. Patel A.A. Yona S. et al.Fine needle aspirates comprehensively sample intrahepatic immunity.Gut. 2019; 68: 1493-1503Crossref PubMed Scopus (46) Google Scholar,[11]Kim J.H. Han J.W. Choi Y.J. Rha M.-S. Koh J.Y. Kim K.H. et al.Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.J Hepatol. 2020; 72: 1170-1181Abstract Full Text Full Text PDF Scopus (29) Google Scholar), to learn more lessons from the "local experts". Prof Maini reports grants from Gilead Science Inc., Immunocore, and F. Hoffmann-La Roche outside the submitted work. The other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.16 MB) Help with pdf files disclosures.pdf