Focal and Local: Ectopic Lymphoid Structures and Aggregates of Myeloid and Other Immune Cells in Liver
2016; Elsevier BV; Volume: 151; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2016.09.029
ISSN1528-0012
AutoresEli Pikarsky, Mathias Heikenwälder,
Tópico(s)Cancer Immunotherapy and Biomarkers
ResumoThe liver functions primarily as a metabolic organ, yet manifests a unique hepatic immune homeostasis that in general is relatively immunosuppressive. This hepatic immune microenvironment is supported by the liver’s unique cellular compositions and architecture.1Protzer U. Maini M.K. Knolle P.A. Living in the liver: hepatic infections.Nature. 2012; 12: 201-213Google Scholar However, it seems that the liver can also host a variety of acute and chronic immunologic reactions and structures manifested as pathologic collections of several different immune cells that likely act in concert in these unique 3-dimensional architectural structures. Such collections can serve as models for understanding the functions of several different ectopic immune cells aggregates.2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 3Haybaeck J. Zeller N. Wolf M.J. et al.A lymphotoxin-driven pathway to hepatocellular carcinoma.Cancer Cell. 2009; 16: 295-308Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 4Huang L.-R. Wohlleber D. Reisinger F. et al.Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.Nature Immunol. 2013; 14: 574-583Crossref PubMed Scopus (173) Google Scholar Two different forms of pathologic hepatic immune cell collections (ectopic lymphoid structures [ELSs] and intrahepatic myeloid aggregates for T-cell expansion [iMATEs]) have been recently described and display unique functional features that have so far not been identified in inflammatory foci located in other nonlymphoid organs.2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 4Huang L.-R. Wohlleber D. Reisinger F. et al.Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.Nature Immunol. 2013; 14: 574-583Crossref PubMed Scopus (173) Google Scholar Focal collections of immune cells are commonly seen in multiple nonlymphoid organs—including the liver—in the context of acute and chronic inflammatory diseases, constructing distinct forms of microanatomic structures. Inflammatory foci can contain adaptive and innate immune cells or display anatomical structures (eg, high endothelial venuoles) usually found in secondary lymphoid organs.5Drayton D.L. Liao S. Mounzer R.H. et al.Lymphoid organ development: from ontogeny to neogenesis.Nature Immunol. 2006; 7: 344-353Crossref PubMed Scopus (538) Google Scholar, 6Wolf M.J. Seleznik G.M. Zeller N. et al.The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development.Oncogene. 2010; 29: 5006-5018Crossref PubMed Scopus (77) Google Scholar Moreover, particular immune cell collections can also constitute new anatomic entities not found under healthy state conditions.2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 4Huang L.-R. Wohlleber D. Reisinger F. et al.Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.Nature Immunol. 2013; 14: 574-583Crossref PubMed Scopus (173) Google Scholar, 7Crispe I.N. Pierce R.H. Killer T cells find meaningful encounters through iMATEs.Nature Immunol. 2013; 14: 533-534Crossref Scopus (2) Google Scholar Notably, these different types of immune cell aggregates can accomplish distinct local immune functions, may they be antiviral, procarcinogenic, or even enable local expansion of immune cell clones (eg, CD8 T cells).2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 4Huang L.-R. Wohlleber D. Reisinger F. et al.Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.Nature Immunol. 2013; 14: 574-583Crossref PubMed Scopus (173) Google Scholar Here we discuss the unique properties of such hepatic focal immune clusters emphasizing the need to better understand how the liver affects these versatile, minute, ectopic “immune organs” and their therapeutic implications. The liver, positioned between the gut with its microflora and the systemic circulation, requires a special immune cell landscape and trafficking that is very much different from those of secondary lymphoid organs as well as other immune-privileged organs (eg, the brain). Unique or highly enriched immune cells in the liver include Kupffer cells, natural killer T cells, liver sinusoid epithelial cells, hepatic stellate cells, and even cholangiocytes and hepatocytes.1Protzer U. Maini M.K. Knolle P.A. Living in the liver: hepatic infections.Nature. 2012; 12: 201-213Google Scholar The unique microarchitecture of fenestration (eg, through sinusoids) enables this dynamic interaction of incoming immune cells with liver sinusoidal endothelial cells, pericytes, and hepatocytes.1Protzer U. Maini M.K. Knolle P.A. Living in the liver: hepatic infections.Nature. 2012; 12: 201-213Google Scholar This shields hepatocytes from direct contact with incoming cells/pathogens, although it also allows room for encounters in the space of Disse, where immune cells interact with hepatocytes, and pericytes can interact with endothelial cells, hepatocytes, or immune cells.1Protzer U. Maini M.K. Knolle P.A. Living in the liver: hepatic infections.Nature. 2012; 12: 201-213Google Scholar, 8Knolle P.A. Wohlleber D. Immunological functions of liver sinusoidal endothelial cells.Cell Mol Immunol. 2016; 13: 347-353Crossref Scopus (106) Google Scholar Thus, this unique environment also reflects the statement of some scientists that the “immunologic clock” in the liver is ticking a bit differently from what we would expect in other organs.1Protzer U. Maini M.K. Knolle P.A. Living in the liver: hepatic infections.Nature. 2012; 12: 201-213Google Scholar It has been known for a long time that classical immunologic organs such as the spleen, lymph nodes, Peyer patches, or even cryptopatches contain well-organized 3-dimensional structures of immune cells, suited for fine-tuning immune responses.9Qi H. Kastenmüller W. Germain R.N. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue.Annu Rev Cell Dev Biol. 2014; 30: 141-167Crossref PubMed Scopus (119) Google Scholar These organized immune cell clusters are of follicular shape and termed white pulp follicles (spleen) or B-cell follicles (lymph nodes). They constitute the functional centers of antigen presentation and clonal immune cell expansion.10Victora G.D. Nussenzweig M.C. Germinal centers.Annu Rev Immunol. 2012; 30: 429-457Crossref PubMed Scopus (1345) Google Scholar In certain pathologic states, both acute and chronic immunologic cells can also form follicular structures, composed of highly organized aggregates of different adaptive and innate immunologic cells that form in situ, termed tertiary lymphoid organs or ELSs. The latter are very likely to execute similar functions as “physiologic” normal follicular immune cells aggregates in secondary lymphoid organs.5Drayton D.L. Liao S. Mounzer R.H. et al.Lymphoid organ development: from ontogeny to neogenesis.Nature Immunol. 2006; 7: 344-353Crossref PubMed Scopus (538) Google Scholar However, in contrast to white pulp follicles or B-cell follicles in secondary lymphoid organs, tertiary lymphoid organs are not developmentally determined and thus can develop theoretically in any organ of the body, such as a local response to an antigen.5Drayton D.L. Liao S. Mounzer R.H. et al.Lymphoid organ development: from ontogeny to neogenesis.Nature Immunol. 2006; 7: 344-353Crossref PubMed Scopus (538) Google Scholar Just as the liver affects the function of diffuse immunologic cell reactions, it could also affect the formation, composition, function, and fate of various focal immunologic reactions and recent evidence suggests that this is the case. Chronic hepatitis is the strongest etiology for liver cancer development and can be triggered by several different pathologies (eg, hepatitis B and C viruses [HBV and HCV], chronic alcohol consumption, chronic high calorie intake combined with a sedentary lifestyle, etc). We and others have shown that ELSs can be found in patients and in mouse models with chronic liver disease.2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 3Haybaeck J. Zeller N. Wolf M.J. et al.A lymphotoxin-driven pathway to hepatocellular carcinoma.Cancer Cell. 2009; 16: 295-308Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 6Wolf M.J. Seleznik G.M. Zeller N. et al.The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development.Oncogene. 2010; 29: 5006-5018Crossref PubMed Scopus (77) Google Scholar Notably, whereas ELSs were found in livers of patients with chronic HCV and (less so) chronic HBV infections as well as in mouse models resembling the inflammatory signature of HBV/HCV infections of human livers, human patients, or mouse models suffering from chronic nonalcoholic steatohepatitis did not display ELSs2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 3Haybaeck J. Zeller N. Wolf M.J. et al.A lymphotoxin-driven pathway to hepatocellular carcinoma.Cancer Cell. 2009; 16: 295-308Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 11Wolf M.J. Adili A. Piotrowitz K. et al.Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.Cancer Cell. 2014; 26: 549-564Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar, 12Bogdanos D.P. Gao B. Gershwin M.E. Liver immunology.Compr Physiol. 2013; 3: 567-598Google Scholar (Figure 1A, B). This emphasizes that the etiology of the chronic hepatic inflammatory environment is very likely to specify the type of intrahepatic inflammation (eg, chronic hepatitis C infection favors ELSs). But what is the role of ELSs in the context of chronic viral infections? Do they positively affect antiviral or anticancer immune responses? With regard to cancer, ELSs have long been associated with good prognosis in other organs, likely due to their ability to facilitate antitumor adaptive immune reactions.13Dieu-Nosjean M.-C. Giraldo N.A. Kaplon H. et al.Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers.Immunol Rev. 2016; 271: 260-275Crossref Scopus (201) Google Scholar This antitumorigenic role was also found in melanoma, and colorectal and lung cancers. Remarkably, we have recently shown that in hepatocellular carcinoma, ELSs are associated with a poor prognosis, in particular late recurrence after hepatocellular carcinoma resection. This indicates that ELSs promoted de novo hepatocarcinogenesis.2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 14Patman G. Hepatocellular carcinoma: ectopic lymphoid structures promote carcinogenesis in the liver.Nat Rev Gastroenterol Hepatol. 2015; 12: 671Crossref Scopus (3) Google Scholar Mechanistically, this was linked with the cytokine-rich milieu present in ELSs, supporting growth of hepatocellular carcinoma progenitor cells within the ELS.2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 15Hoshida Y. Villanueva A. Kobayashi M. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (1034) Google Scholar Here again, the role played by ELSs in the context of hepatic metastases to the liver is not known, yet ELSs can often be seen in hepatic metastases. It remains to be detected in what ways hepatic ELSs are different from ELSs occurring in other nonlymphoid organs and whether these differences underlie the contrasting effects on cancer formation.2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 13Dieu-Nosjean M.-C. Giraldo N.A. Kaplon H. et al.Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers.Immunol Rev. 2016; 271: 260-275Crossref Scopus (201) Google Scholar, 14Patman G. Hepatocellular carcinoma: ectopic lymphoid structures promote carcinogenesis in the liver.Nat Rev Gastroenterol Hepatol. 2015; 12: 671Crossref Scopus (3) Google Scholar In this context, it is interesting to note that regulatory T cells found in tumor associated tertiary lymphoid tissues (eg, in the lung) suppress endogenous immune responses against tumors.16Joshi N.S. Akama-Garren E.H. Lu Y. et al.Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor t cell responses.Immunity. 2015; 43: 579-590Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar Thus, targeting these cells in ELSs might provide therapeutic benefit for cancer patients not only in the lung, but also in the liver. At the same time, it should be noted that the procarcinogenic or anticarcinogenic effects of ELSs in general are controversial (depending on the affected organ) and their role in liver cancer still needs further direct evidence. Our data demonstrate that ELSs seem to have a procarcinogenic effect in the liver,2Finkin S. Yuan D. Stein I. et al.Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.Nature Immunol. 2015; 16: 1235-1244Crossref PubMed Scopus (206) Google Scholar, 3Haybaeck J. Zeller N. Wolf M.J. et al.A lymphotoxin-driven pathway to hepatocellular carcinoma.Cancer Cell. 2009; 16: 295-308Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar yet the direct evidence whether exclusively ELSs or perhaps other intrahepatic immune cells outside ELSs drive liver cancer is missing. Upon entry into the liver, T cells undergo exhaustion, manifested by activation of classical immune checkpoints including PD1 and CTLA4, resulting in T-cell quiescence, dysfunction, and apoptosis.17Wong Y.C. Tay S.S. McCaughan G.W. et al.Immune outcomes in the liver: is CD8 T cell fate determined by the environment?.J Hepatol. 2015; 63: 1005-1014Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar This, of course, could render the liver highly susceptible to infection. iMATEs are collections of myeloid/adaptive immune cells that form in the liver in response to acute viral infection or Toll-like receptor (TLR) activation (eg, TLR-9)4Huang L.-R. Wohlleber D. Reisinger F. et al.Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.Nature Immunol. 2013; 14: 574-583Crossref PubMed Scopus (173) Google Scholar, 7Crispe I.N. Pierce R.H. Killer T cells find meaningful encounters through iMATEs.Nature Immunol. 2013; 14: 533-534Crossref Scopus (2) Google Scholar (Figure 1C, D). These may be regarded as a form of granulomatous reaction, yet giant cells are conspicuously absent. Notably, in contrast to ectopic lymphoid aggregates, iMATEs were insensitive to ablation of LTβR-signaling, strongly supporting iMATEs to be neither of granulomatous nor ectopic lymphoid aggregate origin. Moreover, whereas pathologic collections of myeloid cells (ie, granulomas) are often composed of alternatively activated macrophages (also known as M2 macrophages), iMATE-resident myeloid cells are in part classically activated (M1) macrophages. Notably, in the context of a viral infection virus-specific T cells can proliferate and expand within iMATEs, subsequently leaving the iMATEs to counteract viral infection (Figure 1D). Thus, iMATEs are specialized, myeloid cell–dominated forms of hepatic focal immunity that enables the liver to counteract viral infection, despite the liver’s special immune homeostasis, which favors immunosuppression.4Huang L.-R. Wohlleber D. Reisinger F. et al.Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.Nature Immunol. 2013; 14: 574-583Crossref PubMed Scopus (173) Google Scholar, 7Crispe I.N. Pierce R.H. Killer T cells find meaningful encounters through iMATEs.Nature Immunol. 2013; 14: 533-534Crossref Scopus (2) Google Scholar So far, similarly organized collections of myeloid cells have not been described in other organs, suggesting that the liver plays a critical role in inducing iMATE formation and function. At the same time, it cannot be excluded that also other organs could display iMATE-like structures; however, most likely induced by other mechanisms.7Crispe I.N. Pierce R.H. Killer T cells find meaningful encounters through iMATEs.Nature Immunol. 2013; 14: 533-534Crossref Scopus (2) Google Scholar Interestingly, engaging TLR-9, most likely in hepatocytes, remarkably facilitates the formation of iMATEs. Other TLRs can also induce iMATE formation, but not as efficiently as TLR-9 ligands.4Huang L.-R. Wohlleber D. Reisinger F. et al.Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection.Nature Immunol. 2013; 14: 574-583Crossref PubMed Scopus (173) Google Scholar However, similar to ELSs, the exact mechanisms whereby the formation of iMATEs occurs in the liver, but not in other organs, remain elusive. It is likely that hepatocytes (or other specialized liver cells) play a critical part in recruiting myeloid cells in response to TLR activation and thus confer a T-cell supportive phenotype. Understanding these mechanisms could have important implications for multiple disease states, where it is desirable to abolish immune checkpoint–mediated T-cell suppression, most notably cancer. One wonders whether the frequent occurrence of metastases to the liver may partly be explained by the hepatic T-cell dysfunction, which could then be rectified by induction of iMATEs. There are multiple other more general focal immune reactions that can also occur in the liver. These include abscesses, classical granulomas, wound repair, and necrosis repair, diffusely distributed inflammatory infiltrates and reactions to pathogens of a focal nature.18Leiding J.W. Holland S.M. Chronic Granulomatous Disease.in: Pagon R.A. Adam M.P. Ardinger H.H. Wallace S.E. Amemiya A. Bean L.J.H. Bird T.D. Fong C.T. Mefford H.C. Smith R.J.H. Stephens K. GeneReviews [Internet]. University of Washington, Seattle, Seattle, WA1993-2016Google Scholar In addition, pathologic local immune responses that are considered unique to the liver also exist, such as sclerosing cholangitis, autoimmune hepatitis, and primary biliary cirrhosis (PBC).1Protzer U. Maini M.K. Knolle P.A. Living in the liver: hepatic infections.Nature. 2012; 12: 201-213Google Scholar, 19Sahebjam F. Vierling J.M. Autoimmune hepatitis.Front Med. 2015; 9: 187-219Crossref PubMed Scopus (53) Google Scholar Indeed, ELSs can be detected in several autoimmune liver diseases, such as primary sclerosing cholangitis and PBC.20Chapman R.W. Arborgh B.A. Rhodes J.M. et al.Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology.Gut. 1980; 21: 870-877Crossref PubMed Scopus (679) Google Scholar, 21Alarcn-Segovia D. Diaz-Jouanen E. Fishbein E. Features of Sjögren's syndrome in primary biliary cirrhosis.Ann Intern Med. 1973; 79: 31-36Crossref Google Scholar The exact role of ELSs in primary sclerosing cholangitis or PBC, however, remains elusive. It is speculated that similar to tertiary lymphoid follicles in rheumatoid arthritis, ELSs might provide an environment in which self-antigens can be presented and antigen-specific T cells can be activated, thus enabling maintenance and propagation of autoimmunity. How the composition of ELSs in the context of PBC or primary sclerosing cholangitis differs from ELSs found in chronic HCV or HBV infection and how this affects ELS function (eg, in the context of cancer) is not clear and needs to be determined. We speculate that close inspection of additional focal immune reactions in the liver will reveal that the hepatic microenvironment educates these focal aggregates, and shapes their structure, composition, phenotype and function. Studying these changes could reveal new ways for modulating immune responses, either in the liver, by abolishing the specific liver mechanisms, or systemically, by phenocopying the liver microenvironment in a desired organ.
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