Intestinal Antigen-Presenting Cells
2015; Elsevier BV; Volume: 185; Issue: 7 Linguagem: Inglês
10.1016/j.ajpath.2015.02.024
ISSN1525-2191
AutoresKyle L. Flannigan, Duke Geem, Akihito Harusato, Timothy L. Denning,
Tópico(s)Immune responses and vaccinations
ResumoThe microbiota that populate the mammalian intestine are critical for proper host physiology, yet simultaneously pose a potential danger. Intestinal antigen-presenting cells, namely macrophages and dendritic cells (DCs), are integral components of the mucosal innate immune system that maintain co-existence with the microbiota in face of this constant threat. Intestinal macrophages and DCs integrate signals from the microenvironment to orchestrate innate and adaptive immune responses that ultimately lead to durable tolerance of the microbiota. Tolerance is not a default response, however, because macrophages and DCs remain poised to vigorously respond to pathogens that breach the epithelial barrier. In this review, we summarize the salient features of macrophages and DCs in the healthy and inflamed intestine and discuss how signals from the microbiota can influence their function. The microbiota that populate the mammalian intestine are critical for proper host physiology, yet simultaneously pose a potential danger. Intestinal antigen-presenting cells, namely macrophages and dendritic cells (DCs), are integral components of the mucosal innate immune system that maintain co-existence with the microbiota in face of this constant threat. Intestinal macrophages and DCs integrate signals from the microenvironment to orchestrate innate and adaptive immune responses that ultimately lead to durable tolerance of the microbiota. Tolerance is not a default response, however, because macrophages and DCs remain poised to vigorously respond to pathogens that breach the epithelial barrier. In this review, we summarize the salient features of macrophages and DCs in the healthy and inflamed intestine and discuss how signals from the microbiota can influence their function. From birth, the mammalian intestine is colonized with a complex microbiota leading to a lifelong mutualistic relationship.1Backhed F. Ley R.E. Sonnenburg J.L. Peterson D.A. Gordon J.I. Host-bacterial mutualism in the human intestine.Science. 2005; 307: 1915-1920Crossref PubMed Scopus (3615) Google Scholar This diverse microbial population confers several evolutionary advantages to the host while simultaneously introducing a robust antigenic challenge that has the potential to initiate intestinal inflammation. Despite this threat, the host manages to maintain intestinal homeostasis via a sophisticated immune cell network that promotes tolerance to the microbiota while permitting responsiveness to invading pathogens.2Maloy K.J. Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease.Nature. 2011; 474: 298-306Crossref PubMed Scopus (1285) Google Scholar, 3Mowat A.M. Agace W.W. Regional specialization within the intestinal immune system.Nat Rev Immunol. 2014; 14: 667-685Crossref PubMed Scopus (842) Google Scholar Central to this discrimination process are intestinal antigen-presenting cells (APCs), predominantly composed of macrophages and dendritic cells (DCs), that are separated from the microbiota by a single layer of epithelial cells. Together, intestinal macrophages and DCs integrate cues from epithelial, immune, and stromal cells to direct innate and adaptive immunity.4Bain C.C. Mowat A.M. Macrophages in intestinal homeostasis and inflammation.Immunol Rev. 2014; 260: 102-117Crossref PubMed Scopus (370) Google Scholar, 5Bain C.C. Mowat A.M. Intestinal macrophages: specialised adaptation to a unique environment.Eur J Immunol. 2011; 41: 2494-2498Crossref PubMed Scopus (80) Google Scholar, 6Coombes J.L. Powrie F. Dendritic cells in intestinal immune regulation.Nat Rev Immunol. 2008; 8: 435-446Crossref PubMed Scopus (604) Google Scholar, 7Mowat A.M. 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Interactions between the host innate immune system and microbes in inflammatory bowel disease.Gastroenterology. 2011; 140: 1729-1737Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar This review will focus on the role of intestinal macrophages and DCs in the steady state and during inflammation, as well as how these cells interface with the microbiota. The tissue microenvironment plays a key role in regulating the differentiation of macrophages and DCs from myeloid progenitor cells. In the intestine, the local milieu is shaped by the microbiota, enteric antigens, and immune cells that collectively contribute to the developmental outcome of macrophage and DC precursors entering the intestine. Intestinal macrophages, for example, are maintained and replenished by Ly6C+ monocytes that continually enter the intestine during the steady state and inflammation, a process referred to as the monocyte waterfall. These Ly6C+ monocytes subsequently differentiate into resident intestinal macrophages through a series of intermediary stages.12Bain C.C. Bravo-Blas A. Scott C.L. Gomez Perdiguero E. Geissmann F. Henri S. Malissen B. Osborne L.C. Artis D. Mowat A.M. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice.Nat Immunol. 2014; 15: 929-937Crossref PubMed Scopus (703) Google Scholar, 13Bain C.C. Scott C.L. Uronen-Hansson H. Gudjonsson S. Jansson O. Grip O. Guilliams M. Malissen B. Agace W.W. Mowat A.M. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors.Mucosal Immunol. 2013; 6: 498-510Crossref PubMed Scopus (588) Google Scholar, 14Tamoutounour S. Henri S. Lelouard H. de Bovis B. de Haar C. van der Woude C.J. Woltman A.M. Reyal Y. Bonnet D. Sichien D. Bain C.C. Mowat A.M. Reis e Sousa C. Poulin L.F. Malissen B. Guilliams M. CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis.Eur J Immunol. 2012; 42: 3150-3166Crossref PubMed Scopus (368) Google Scholar, 15Zigmond E. Varol C. Farache J. Elmaliah E. Satpathy A.T. Friedlander G. Mack M. Shpigel N. Boneca I.G. Murphy K.M. Shakhar G. Halpern Z. Jung S. Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells.Immunity. 2012; 37: 1076-1090Abstract Full Text Full Text PDF PubMed Scopus (502) Google Scholar The monocytes that produce intestinal macrophages are originally derived from macrophage-DC progenitors, which are the same bone marrow progenitors that can produce intestinal DCs.16Fogg D.K. Sibon C. Miled C. Jung S. Aucouturier P. Littman D.R. Cumano A. Geissmann F. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells.Science. 2006; 311: 83-87Crossref PubMed Scopus (774) Google Scholar The ultimate fate of macrophage-DC progenitors in the intestine is, thus, determined by specific cytokines and growth factors in the tissue microenvironment that dictate different developmental programs. The maturation of monocytes that produce intestinal macrophages is under the control of the colony-stimulating factor 1 (Csf1) receptor and its stimulation by Csf1. Accordingly, the number of intestinal macrophages is significantly reduced in Csf1 receptor–deficient mice17Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. Stanley E.R. Nussenzweig M. Lira S.A. Randolph G.J. Merad M. Origin of the lamina propria dendritic cell network.Immunity. 2009; 31: 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar and in mice treated with anti-Csf1 receptor antibody.18MacDonald K.P. Palmer J.S. Cronau S. Seppanen E. Olver S. Raffelt N.C. Kuns R. Pettit A.R. Clouston A. Wainwright B. Branstetter D. Smith J. Paxton R.J. Cerretti D.P. Bonham L. Hill G.R. Hume D.A. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation.Blood. 2010; 116: 3955-3963Crossref PubMed Scopus (331) Google Scholar Csf1op/op mice, which have a mutation in the gene encoding Csf1, also have markedly reduced numbers of intestinal macrophages.19Ryan G.R. Dai X.M. Dominguez M.G. Tong W. Chuan F. Chisholm O. Russell R.G. Pollard J.W. Stanley E.R. Rescue of the colony-stimulating factor 1 (CSF-1)-nullizygous mouse (Csf1(op)/Csf1(op)) phenotype with a CSF-1 transgene and identification of sites of local CSF-1 synthesis.Blood. 2001; 98: 74-84Crossref PubMed Scopus (184) Google Scholar Macrophage-DC progenitors can alternatively differentiate into common DC progenitors that are the precursors of conventional DCs and plasmacytoid DCs. Common DC progenitors can produce pre-DCs that develop into peripheral DCs, including intestinal CD103+ DCs, in a FMS-like tyrosine kinase 3 (Flt3)–dependent manner.17Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. Stanley E.R. Nussenzweig M. Lira S.A. Randolph G.J. Merad M. Origin of the lamina propria dendritic cell network.Immunity. 2009; 31: 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar Thus, intestinal CD103+ DCs expand in vivo in response to Flt3L20Varol C. Vallon-Eberhard A. Elinav E. Aychek T. Shapira Y. Luche H. Fehling H.J. Hardt W.D. Shakhar G. Jung S. Intestinal lamina propria dendritic cell subsets have different origin and functions.Immunity. 2009; 31: 502-512Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar and are substantially decreased in mice deficient for Flt3 or Flt3L.17Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. Stanley E.R. Nussenzweig M. Lira S.A. Randolph G.J. Merad M. Origin of the lamina propria dendritic cell network.Immunity. 2009; 31: 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar Other growth factors can further influence the homeostasis of different subsets of DCs, as highlighted by data demonstrating that CD103+CD11b+ intestinal DCs require Csf2 receptor stimulation via Csf2 (formerly granulocyte-macrophage colony-stimulating factor) for development in the steady state; however, this factor is dispensable for the differentiation of inflammatory DCs.17Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. Stanley E.R. Nussenzweig M. Lira S.A. Randolph G.J. Merad M. Origin of the lamina propria dendritic cell network.Immunity. 2009; 31: 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar The future identification of additional mediators that control macrophage and DC development may further our understanding of their ontogeny. Studies investigating intestinal macrophage and DC development have gained support from recent advancements in the phenotypic characterization of these cells. Analyses of cell morphology and surface markers have allowed for the clear distinction of intestinal macrophages and DCs from one another as well as the definition of different subsets of each population. When examining cellular structure, macrophages can typically be identified by the presence of large phagocytic vacuoles in the cytoplasm, whereas DCs exhibit dendrite-like projections.5Bain C.C. Mowat A.M. Intestinal macrophages: specialised adaptation to a unique environment.Eur J Immunol. 2011; 41: 2494-2498Crossref PubMed Scopus (80) Google Scholar In addition to microscopy, multicolor flow cytometry has been instrumental in distinguishing intestinal macrophage and DC populations from each other, as well as from additional cell types. Clear identification of APCs from collagenase-digested intestinal cells can be achieved by inclusion of the two core markers: CD45, to select for leukocytes, and major histocompatibility complex (MHC) II, to mark cells with exogenous antigen-presenting ability. Additional markers can then be used to define populations of macrophages and DCs. Initial work investigating cell surface markers expressed by intestinal APCs relied on the presence of F4/80 and the alpha X integrin, CD11c. F4/80 has long-standing use as a macrophage-specific marker and, when used in combination with the core APC markers, CD45 and MHCII, can discern macrophages from DCs in the healthy intestine.21Hume D.A. Robinson A.P. MacPherson G.G. Gordon S. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: relationship between macrophages, Langerhans cells, reticular cells, and dendritic cells in lymphoid and hematopoietic organs.J Exp Med. 1983; 158: 1522-1536Crossref PubMed Scopus (304) Google Scholar On the other hand, the utility of CD11c as a DC-specific marker is limited because of the fact that intestinal macrophages and DCs both express moderate to high levels of this antigen, precluding clear delineation of DCs from macrophages in the intestine.4Bain C.C. Mowat A.M. Macrophages in intestinal homeostasis and inflammation.Immunol Rev. 2014; 260: 102-117Crossref PubMed Scopus (370) Google Scholar, 5Bain C.C. Mowat A.M. Intestinal macrophages: specialised adaptation to a unique environment.Eur J Immunol. 2011; 41: 2494-2498Crossref PubMed Scopus (80) Google Scholar, 7Mowat A.M. Bain C.C. Mucosal macrophages in intestinal homeostasis and inflammation.J Innate Immun. 2011; 3: 550-564Crossref PubMed Scopus (168) Google Scholar, 22Denning T.L. Norris B.A. Medina-Contreras O. Manicassamy S. Geem D. Madan R. Karp C.L. Pulendran B. Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization.J Immunol. 2011; 187: 733-747Crossref PubMed Scopus (249) Google Scholar, 23Denning T.L. Wang Y.C. Patel S.R. Williams I.R. Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses.Nat Immunol. 2007; 8: 1086-1094Crossref PubMed Scopus (802) Google Scholar A similarly complex issue exists with regard to CD11b because it is expressed by nearly all macrophages, but also a subset of intestinal DCs as well as eosinophils and neutrophils.7Mowat A.M. Bain C.C. Mucosal macrophages in intestinal homeostasis and inflammation.J Innate Immun. 2011; 3: 550-564Crossref PubMed Scopus (168) Google Scholar To ensure exclusion of these cells, the eosinophil-specific marker, Siglec-F, and the neutrophil-specific marker, Ly6G, can be used during analysis of intestinal macrophages and DCs. Another marker that has gained particular attention on intestinal APCs is CX3 chemokine receptor 1 (CR1), which is involved in the extension of transepithelial dendrites into the intestinal lumen during bacterial infection.24Niess J.H. Brand S. Gu X. Landsman L. Jung S. McCormick B.A. Vyas J.M. Boes M. Ploegh H.L. Fox J.G. Littman D.R. Reinecker H.C. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance.Science. 2005; 307: 254-258Crossref PubMed Scopus (1287) Google Scholar Although CX3CR1 is highly expressed on resident intestinal macrophages25Medina-Contreras O. Geem D. Laur O. Williams I.R. Lira S.A. Nusrat A. Parkos C.A. Denning T.L. CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice.J Clin Invest. 2011; 121: 4787-4795Crossref PubMed Scopus (216) Google Scholar, 26Schulz O. Jaensson E. Persson E.K. Liu X. Worbs T. Agace W.W. Pabst O. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions.J Exp Med. 2009; 206: 3101-3114Crossref PubMed Scopus (546) Google Scholar that are located in the lamina propria, as well as the smooth muscle layer of the intestine,17Bogunovic M. Ginhoux F. Helft J. Shang L. Hashimoto D. Greter M. Liu K. Jakubzick C. Ingersoll M.A. Leboeuf M. Stanley E.R. Nussenzweig M. Lira S.A. Randolph G.J. Merad M. Origin of the lamina propria dendritic cell network.Immunity. 2009; 31: 513-525Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar it can also be expressed at intermediate levels by some DCs during inflammation.13Bain C.C. Scott C.L. Uronen-Hansson H. Gudjonsson S. Jansson O. Grip O. Guilliams M. Malissen B. Agace W.W. Mowat A.M. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors.Mucosal Immunol. 2013; 6: 498-510Crossref PubMed Scopus (588) Google Scholar, 27Rivollier A. He J. Kole A. Valatas V. Kelsall B.L. Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon.J Exp Med. 2012; 209: 139-155Crossref PubMed Scopus (421) Google Scholar The high-affinity IgG receptor, CD64, has also been used to specifically identify intestinal macrophages.7Mowat A.M. Bain C.C. Mucosal macrophages in intestinal homeostasis and inflammation.J Innate Immun. 2011; 3: 550-564Crossref PubMed Scopus (168) Google Scholar, 14Tamoutounour S. Henri S. Lelouard H. de Bovis B. de Haar C. van der Woude C.J. Woltman A.M. Reyal Y. Bonnet D. Sichien D. Bain C.C. Mowat A.M. Reis e Sousa C. Poulin L.F. Malissen B. Guilliams M. CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis.Eur J Immunol. 2012; 42: 3150-3166Crossref PubMed Scopus (368) Google Scholar Beyond F4/80, CD11b, CX3CR1, and CD64, intestinal macrophages can also be further identified by the differential expression of CD14, CD68, and Toll-like receptor (TLR)2.7Mowat A.M. Bain C.C. Mucosal macrophages in intestinal homeostasis and inflammation.J Innate Immun. 2011; 3: 550-564Crossref PubMed Scopus (168) Google Scholar Resident intestinal DCs can be distinguished from macrophages primarily by their expression of CD103 and lack of CX3CR1.22Denning T.L. Norris B.A. Medina-Contreras O. Manicassamy S. Geem D. Madan R. Karp C.L. Pulendran B. Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization.J Immunol. 2011; 187: 733-747Crossref PubMed Scopus (249) Google Scholar, 26Schulz O. Jaensson E. Persson E.K. Liu X. Worbs T. Agace W.W. Pabst O. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions.J Exp Med. 2009; 206: 3101-3114Crossref PubMed Scopus (546) Google Scholar CD103+CX3CR1− DCs can further be divided into CD11b+ and CD11b− subsets, both of which express CCR7 and can migrate to mesenteric lymph nodes (mLNs) and imprint gut-homing markers on naïve T cells.26Schulz O. Jaensson E. Persson E.K. Liu X. Worbs T. Agace W.W. Pabst O. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions.J Exp Med. 2009; 206: 3101-3114Crossref PubMed Scopus (546) Google Scholar Therefore, at the steady state, intestinal DCs can be defined among APCs (CD45+MHCII+) as CD11b+/−CD11c+F4/80−CD103+CX3CR1−CD64− cells and may be contrasted from macrophages, which are CD11b+CD11c+/−F4/80+CD103−CX3CR1+CD64+ cells (Figure 1).13Bain C.C. Scott C.L. Uronen-Hansson H. Gudjonsson S. Jansson O. Grip O. Guilliams M. Malissen B. Agace W.W. Mowat A.M. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors.Mucosal Immunol. 2013; 6: 498-510Crossref PubMed Scopus (588) Google Scholar, 22Denning T.L. Norris B.A. Medina-Contreras O. Manicassamy S. Geem D. Madan R. Karp C.L. Pulendran B. Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization.J Immunol. 2011; 187: 733-747Crossref PubMed Scopus (249) Google Scholar In addition to this panel, intestinal DCs can also be further identified by CD272 and CD26 expression.28Scott C.L. Bain C.C. Wright P.B. Sichien D. Kotarsky K. Persson E.K. Luda K. Guilliams M. Lambrecht B.N. Agace W.W. Milling S.W. Mowat A.M. CCR2(+)CD103(-) intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production by T cells.Mucosal Immunol. 2015; 8: 327-339Crossref PubMed Scopus (120) Google Scholar Collectively, these markers can also be used in complex scenarios, such as inflammation; however, certain cell surface antigens can change expression in the presence of inflammatory stimuli. 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In these studies, specific deletion of IL-10R, but not IL-10 itself, in CX3CR1+ resident macrophages led to the development of spontaneous colitis.32Zigmond E. Bernshtein B. Friedlander G. Walker C.R. Yona S. Kim K.W. Brenner O. Krauthgamer R. Varol C. Muller W. Jung S. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis.Immunity. 2014; 40: 720-733Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar Functional analyses found that IL-10R–deficient macrophages displayed exaggerated proinflammatory responses with little IL-10 production.33Shouval D.S. Biswas A. Goettel J.A. McCann K. Conaway E. Redhu N.S. Mascanfroni I.D. Al Adham Z. Lavoie S. Ibourk M. Nguyen D.D. Samsom J.N. Escher J.C. Somech R. Weiss B. Beier R. Conklin L.S. Ebens C.L. Santos F.G. Ferreira A.R. Sherlock M. Bhan A.K. Muller W. Mora J.R. Quintana F.J. Klein C. Muise A.M. Horwitz B.H. Snapper S.B. 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