Key Points
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The structure of the spleen is such that two compartments can be distinguished: the blood-containing red pulp; and the white pulp, which is full of lymphoid cells.
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In the red pulp, pathogens and cellular debris, as well as ageing erythrocytes, are efficiently removed from the blood by macrophages, which are abundant in this compartment. These macrophages are then well equipped to recycle iron from the erythrocytes.
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The white pulp is a highly organized lymphoid region where adaptive immune responses can be initiated. It is composed of separate areas for B cells and T cells, which are surrounded by the marginal zone — a region that contains discrete subsets of macrophages and B cells. Whereas blood flows freely through the marginal zone, the white pulp is excluded from the bloodstream, and specific signals are required for entry.
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Entry of leukocytes to the white pulp requires activation of G-protein-coupled receptors, a process which is reminiscent of the multistep extravasation process that has been described for leukocytes leaving the bloodstream and entering the lymph nodes or sites of inflammation.
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The marginal zone forms a bridge between the innate and adaptive immune response, because the macrophages in this region, which express specific pattern-recognition receptors, can efficiently take up blood-borne pathogens. The specific subset of B cells in this region, the marginal-zone B cells, can be activated by these macrophages or can directly respond to blood-borne pathogens, after which they become antigen-presenting cells or IgM-producing plasma cells.
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Entry of activated dendritic cells or marginal-zone B cells to the white pulp can initiate an adaptive immune response through activation of T cells, which then migrate to the edge of the B-cell follicles and provide help to B cells.
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The organization of the white pulp into distinct areas, which promotes efficient interaction of cells of the immune system, is coordinated by the expression of chemokines, which attract the specific lymphoid subsets to the appropriate microdomains.
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In addition, the organization of both the white pulp and the marginal zone is under strict control of lipid mediators and adhesion molecules, as well as chemokines, all of which help the specific cellular subsets to be retained within their compartments. Expression of these factors is, in turn, controlled by activation of the lymphotoxin-β receptor and tumour-necrosis-factor receptor 1, but it might also involve additional signalling receptors.
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Through this unique organization of its compartments, the spleen can mount complex adaptive immune responses, as well as effectively clear pathogens from the blood.
Abstract
The spleen combines the innate and adaptive immune system in a uniquely organized way. The structure of the spleen enables it to remove older erythrocytes from the circulation and leads to the efficient removal of blood-borne microorganisms and cellular debris. This function, in combination with a highly organized lymphoid compartment, makes the spleen the most important organ for antibacterial and antifungal immune reactivity. A better understanding of the function of this complex organ has been gained from recent studies, as outlined in this Review article.
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References
Kraal, G. Cells in the marginal zone of the spleen. Int. Rev. Cytol. 132, 31–73 (1992).
Steiniger, B. & Barth, P. Microanatomy and function of the spleen. Adv. Anat. Embryol. Cell Biol. 151, III–IX; 1–101 (2000).
Groom, A. C., Schmidt, E. E. & MacDonald, I. C. Microcirculatory pathways and blood flow in spleen: new insights from washout kinetics, corrosion casts, and quantitative intravital videomicroscopy. Scanning Microsc. 5, 159–174 (1991).
Drenckhahn, D. & Wagner, J. Stress fibers in the splenic sinus endothelium in situ: molecular structure, relationship to the extracellular matrix, and contractility. J. Cell Biol. 102, 1738–1747 (1986).
MacDonald, I. C., Ragan, D. M., Schmidt, E. E. & Groom, A. C. Kinetics of red blood cell passage through interendothelial slits into venous sinuses in rat spleen, analyzed by in vivo microscopy. Microvasc. Res. 33, 118–134 (1987).
Bratosin, D. et al. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie 80, 173–195 (1998).
Stewart, I. B. & McKenzie, D. C. The human spleen during physiological stress. Sports Med. 32, 361–369 (2002).
Knutson, M. & Wessling-Resnick, M. Iron metabolism in the reticuloendothelial system. Crit. Rev. Biochem. Mol. Biol. 38, 61–88 (2003).
Maines, M. D. The heme oxygenase system: a regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 37, 517–554 (1997).
Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001). This paper shows that CD163, which is expressed at the cell surface of macrophages, is a scavenger receptor for haemoglobin and haptoglobin-bound haemoglobin. This provides insight into a molecular mechanism of iron recycling by macrophages.
Gruenheid, S. et al. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J. Exp. Med. 189, 831–841 (1999).
Gruenheid, S. & Gros, P. Genetic susceptibility to intracellular infections: Nramp1, macrophage function and divalent cations transport. Curr. Opin. Microbiol. 3, 43–48 (2000).
Hackam, D. J. et al. Host resistance to intracellular infection: mutation of natural resistance-associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J. Exp. Med. 188, 351–364 (1998).
Ratledge, C. & Dover, L. G. Iron metabolism in pathogenic bacteria. Annu. Rev. Microbiol. 54, 881–941 (2000).
Flo, T. H. et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432, 917–921 (2004). The authors of this paper describe a new mechanism of the control of bacterial growth by macrophages, the increased production of lipocalin-2 after bacterial encounter. This molecule sequesters iron and thereby limits the growth of bacteria.
Sze, D. M., Toellner, K. M., Garcia de Vinuesa, C., Taylor, D. R. & MacLennan, I. C. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J. Exp. Med. 192, 813–821 (2000).
MacLennan, I. C. et al. Extrafollicular antibody responses. Immunol. Rev. 194, 8–18 (2003).
Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).
Garcia De Vinuesa, C. et al. Dendritic cells associated with plasmablast survival. Eur. J. Immunol. 29, 3712–3721 (1999).
Leenen, P. J. M. et al. Heterogeneity of mouse spleen dendritic cells: in vivo phagocytic activity, expression of macrophage markers, and subpopulation turnover. J. Immunol. 160, 2166–2173 (1998).
Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).
Gunn, M. D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).
Förster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).
Ngo, V. N. et al. Lymphotoxin α/β and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189, 403–412 (1999).
Matsumoto, M. et al. Role of lymphotoxin and the type I TNF receptor in the formation of germinal centers. Science 271, 1289–1291 (1996).
Mebius, R. E., Van Tuijl, S., Weissman, I. L. & Randall, T. D. Transfer of primitive stem/progenitor bone marrow cells from LT-α−/− donors to wild-type hosts: implications for the generation of architectural events in lymphoid B cell domains. J. Immunol. 161, 3836–3843 (1998).
Endres, R. et al. Mature follicular dendritic cell networks depend on expression of lymphotoxin β receptor by radioresistant stromal cells and of lymphotoxin β and tumor necrosis factor by B cells. J. Exp. Med. 189, 159–168 (1999).
Luther, S. A., Tang, H. L., Hyman, P. L., Farr, A. G. & Cyster, J. G. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc. Natl Acad. Sci. USA 97, 12694–12699 (2000).
Ngo, V. N., Cornall, R. J. & Cyster, J. G. Splenic T zone development is B cell dependent. J. Exp. Med. 194, 1649–1660 (2001).
Tumanov, A. et al. Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. Immunity 17, 239–250 (2002).
Cyster, J. G. & Goodnow, C. C. Pertussis toxin inhibits migration of B and T lymphocytes into splenic white pulp cords. J. Exp. Med. 182, 581–586 (1995). In this paper, the authors show that entry of lymphocytes to the white pulp depends on signalling through G-protein-coupled receptors.
Johnston, B. & Butcher, E. C. Chemokines in rapid leukocyte adhesion triggering and migration. Semin. Immunol. 14, 83–92 (2002).
Kang, Y. S. et al. The C-type lectin SIGN-R1 mediates uptake of the capsular polysaccharide of Streptococcus pneumoniae in the marginal zone of mouse spleen. Proc. Natl Acad. Sci. USA 101, 215–220 (2004).
Kang, Y. S. et al. SIGN-R1, a novel C-type lectin expressed by marginal zone macrophages in spleen, mediates uptake of the polysaccharide dextran. Int. Immunol. 15, 177–186 (2003).
Geijtenbeek, T. B. et al. Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo. Blood 100, 2908–2916 (2002). This paper shows that expression of the mouse homologue of DC-SIGN, SIGNR1, is restricted in the spleen to marginal-zone macrophages. It functions there as a pattern-recognition receptor for blood-borne antigens.
Elomaa, O. et al. Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages. Cell 80, 603–609 (1995).
Munday, J., Floyd, H. & Crocker, P. R. Sialic acid binding receptors (siglecs) expressed by macrophages. J. Leukoc. Biol. 66, 705–711 (1999).
Yu, P. et al. B cells control the migration of a subset of dendritic cells into B cell follicles via CXC chemokine ligand 13 in a lymphotoxin-dependent fashion. J. Immunol. 168, 5117–5123 (2002).
Martin, F. & Kearney, J. F. Marginal-zone B cells. Nature Rev. Immunol. 2, 323–335 (2002).
Nolte, M. A. et al. B cells are crucial for both development and maintenance of the splenic marginal zone. J. Immunol. 172, 3620–3627 (2004).
Crowley, M. T., Reilly, C. R. & Lo, D. Influence of lymphocytes on the presence and organization of dendritic cell subsets in the spleen. J. Immunol. 163, 4894–4900 (1999).
Cupedo, T. et al. Initiation of cellular organization in lymph nodes is regulated by non-B cell-derived signals and is not dependent on CXC chemokine ligand 13. J. Immunol. 173, 4889–4896 (2004).
Cupedo, T. et al. Presumptive lymph node organizers are differentially represented in developing mesenteric and peripheral nodes. J. Immunol. 173, 2968–2975 (2004).
Ato, M., Nakano, H., Kakiuchi, T. & Kaye, P. M. Localization of marginal zone macrophages is regulated by C-C chemokine ligands 21/19. J. Immunol. 173, 4815–4820 (2004).
Karlsson, M. C. et al. Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J. Exp. Med. 198, 333–340 (2003).
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).
Allende, M. L., Dreier, J. L., Mandala, S. & Proia, R. L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004).
Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nature Immunol. 5, 713–720 (2004). This paper shows that S1P 1 is required for retention of marginal-zone B cells in the marginal zone, 'overwriting' the effects of the chemoattractant CXCL13, which is produced in B-cell follicles. This finding adds another level of complexity to the regulation of the integrity of the marginal zone.
Girkontaite, I. et al. The sphingosine-1-phosphate (S1P) lysophospholipid receptor S1P3 regulates MAdCAM-1+ endothelial cells in splenic marginal sinus organization. J. Exp. Med. 200, 1491–1501 (2004).
Graeler, M., Shankar, G. & Goetzl, E. J. Suppression of T cell chemotaxis by sphingosine 1-phosphate. J. Immunol. 169, 4084–4087 (2002).
Goetzl, E. J., Wang, W., McGiffert, C., Huang, M. C. & Graler, M. H. Sphingosine 1-phosphate and its G protein-coupled receptors constitute a multifunctional immunoregulatory system. J. Cell. Biochem. 92, 1104–1114 (2004).
Lu, T. T. & Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002).
Guinamard, R., Okigaki, M., Schlessinger, J. & Ravetch, J. V. Absence of marginal zone B cells in Pyk-2 deficient mice defines their role in the humoral response. Nature Immunol. 1, 31–36 (2000).
Gordon, S. Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927–930 (2002).
Koppel, E. A. et al. Identification of the mycobacterial carbohydrate structure that binds the C-type lectins DC-SIGN, L-SIGN and SIGNR1. Immunobiology 209, 117–127 (2004).
Lanoue, A. et al. SIGN-R1 contributes to protection against lethal pneumococcal infection in mice. J. Exp. Med. 200, 1383–1393 (2004).
Marzi, A. et al. DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus. J. Virol. 78, 12090–12095 (2004).
Oehen, S. et al. Marginal zone macrophages and immune responses against viruses. J. Immunol. 169, 1453–1458 (2002).
Crocker, P. R. & Varki, A. Siglecs, sialic acids and innate immunity. Trends Immunol. 22, 337–342 (2001).
Jones, C., Virji, M. & Crocker, P. R. Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake. Mol. Microbiol. 49, 1213–1225 (2003).
Eloranta, M. L. & Alm, G. V. Splenic marginal metallophilic macrophages and marginal zone macrophages are the major interferon-α/β producers in mice upon intravenous challenge with herpes simplex virus. Scand. J. Immunol. 49, 391–394 (1999).
Van Rooijen, N. Antigen processing and presentation in vivo: the microenvironment as a crucial factor. Immunol. Today 11, 436–439 (1990).
Lopes-Carvalho, T. & Kearney, J. F. Development and selection of marginal zone B cells. Immunol. Rev. 197, 192–205 (2004).
Attanavanich, K. & Kearney, J. F. Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J. Immunol. 172, 803–811 (2004).
Ato, M., Stager, S., Engwerda, C. R. & Kaye, P. M. Defective CCR7 expression on dendritic cells contributes to the development of visceral leishmaniasis. Nature Immunol. 3, 1185–1191 (2002).
Amlot, P. L. & Hayes, A. E. Impaired human antibody response to the thymus-independent antigen, DNP–Ficoll, after splenectomy. Implications for post-splenectomy infections. Lancet 1, 1008–1011 (1985).
Nolte, M. A., Hoen, E. N., van Stijn, A., Kraal, G. & Mebius, R. E. Isolation of the intact white pulp. Quantitative and qualitative analysis of the cellular composition of the splenic compartments. Eur. J. Immunol. 30, 626–634 (2000). This paper shows, by isolation of intact white pulp, that the cellular composition and organization of the lymphoid compartment of the spleen is highly similar to that of lymph nodes.
Balazs, M., Martin, F., Zhou, T. & Kearney, J. Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity 17, 341–352 (2002).
Ansel, K. M., McHeyzer-Williams, L. J., Ngo, V. N., McHeyzer-Williams, M. G. & Cyster, J. G. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190, 1123–1134 (1999).
Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416, 94–99 (2002).
Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998).
Pape, K. A. et al. Visualization of the genesis and fate of isotype-switched B cells during a primary immune response. J. Exp. Med. 197, 1677–1687 (2003).
Gretz, J. E., Norbury, C. C., Anderson, A. O., Proudfoot, A. E. I. & Shaw, S. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. J. Exp. Med. 192, 1425–1440 (2000). The authors show that there is a fine tubular network in the lymph nodes that allows rapid transport of small molecules. Others have shown that this conduit system is important for the transport of chemokines and that it is also present in the spleen.
Nolte, M. A. et al. A conduit system distributes chemokines and small blood-borne molecules through the splenic white pulp. J. Exp. Med. 198, 505–512 (2003).
Palframan, R. T. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1373 (2001).
Baekkevold, E. S. et al. The CCR7 ligand ELC (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment. J. Exp. Med. 193, 1105–1112 (2001).
Sixt, M. et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22, 19–29 (2005).
Katakai, T., Hara, T., Sugai, M., Gonda, H. & Shimizu, A. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. J. Exp. Med. 200, 783–795 (2004).
Dejardin, E. et al. The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17, 525–535 (2002).
Unsoeld, H., Voehringer, D., Krautwald, S. & Pircher, H. Constitutive expression of CCR7 directs effector CD8 T cells into the splenic white pulp and impairs functional activity. J. Immunol. 173, 3013–3019 (2004).
Mitchell, J. Lymphocyte circulation in the spleen. Marginal zone bridging channels and their possible role in cell traffic. Immunology 24, 93–107 (1973).
Green, M. C. A defect of the splanchnic mesoderm caused by the mutant gene dominant hemimelia in the mouse. Dev. Biol. 15, 62–89 (1967).
Hecksher-Sorensen, J. et al. The splanchnic mesodermal plate directs spleen and pancreatic laterality, and is regulated by Bapx1/Nkx3.2. Development 131, 4665–4675 (2004).
Roberts, C. W., Shutter, J. R. & Korsmeyer, S. J. Hox11 controls the genesis of the spleen. Nature 368, 747–749 (1994).
Lu, J. et al. The basic helix–loop–helix transcription factor capsulin controls spleen organogenesis. Proc. Natl Acad. Sci. USA 97, 9525–9530 (2000).
Herzer, U., Crocoll, A., Barton, D., Howells, N. & Englert, C. The Wilms tumor suppressor gene WT1 is required for development of the spleen. Curr. Biol. 9, 837–840 (1999).
Seifert, M. F. & Marks, S. C. J. The regulation of hemopoiesis in the spleen. Experientia 41, 192–199 (1985).
Mebius, R., Rennert, P. D. & Weissman, I. L. Developing lymph nodes collect CD4+CD3− LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504 (1997).
Mebius, R. E. Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003).
Saito, T. et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18, 675–685 (2003).
Quong, M. W. et al. Receptor editing and marginal zone B cell development are regulated by the helix–loop–helix protein, E2A. J. Exp. Med. 199, 1101–1112 (2004).
Tanigaki, K. et al. Notch–RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nature Immunol. 3, 443–450 (2002).
Kuroda, K. et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18, 301–312 (2003).
Cariappa, A. et al. The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 14, 603–615 (2001).
Loder, F. et al. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J. Exp. Med. 190, 75–89 (1999). References 90–95 provide evidence that the differentiation of B cells into marginal-zone B cells or follicular B cells is a cell-fate decision that is regulated by many factors.
Makowska, A., Faizunnessa, N. N., Anderson, P., Midtvedt, T. & Cardell, S. CD1high B cells: a population of mixed origin. Eur. J. Immunol. 29, 3285–3294 (1999).
Pillai, S., Cariappa, A. & Moran, S. T. Marginal zone B cells. Annu. Rev. Immunol. 23, 161–196 (2005).
Steiniger, B., Ruttinger, L. & Barth, P. J. The three-dimensional structure of human splenic white pulp compartments. J. Histochem. Cytochem. 51, 655–664 (2003).
Steiniger, B., Barth, P. & Hellinger, A. The perifollicular and marginal zones of the human splenic white pulp: do fibroblasts guide lymphocyte immigration? Am. J. Pathol. 159, 501–512 (2001).
De Togni, P. et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).
Banks, T. A. et al. Lymphotoxin-α-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J. Immunol. 155, 1685–1693 (1995).
Koni, P. A. et al. Distinct roles in lymphoid organogenesis for lymphotoxins α and β revealed in lymphotoxin β-deficient mice. Immunity 6, 491–500 (1997).
Alexopoulou, L., Pasparakis, M. & Kollias, G. Complementation of lymphotoxin α knockout mice with tumor necrosis factor-expressing transgenes rectifies defective splenic structure and function. J. Exp. Med. 188, 745–754 (1998).
Pasparakis, M., Kousteni, S., Peschon, J. & Kollias, G. Tumor necrosis factor and the p55TNF receptor are required for optimal development of the marginal sinus and for migration of follicular dendritic cell precursors into splenic follicles. Cell. Immunol. 201, 33–41 (2000).
Kuprash, D. V. et al. TNF and lymphotoxin β cooperate in the maintenance of secondary lymphoid tissue microarchitecture but not in the development of lymph nodes. J. Immunol. 163, 6575–6580 (1999).
Alimzhanov, M. et al. Abnormal development of secondary lymphoid tissues in lymphotoxin β-deficient mice. Proc. Natl Acad. Sci. USA 94, 9302–9307 (1997).
Kuprash, D. V. et al. Redundancy in tumor necrosis factor (TNF) and lymphotoxin (LT) signaling in vivo: mice with inactivation of the entire TNF/LT locus versus single-knockout mice. Mol. Cell. Biol. 22, 8626–8634 (2002).
Futterer, A., Mink, K., Luz, A., Kosco-Vilbois, M. H. & Pfeffer, K. The lymphotoxin β receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9, 59–70 (1998).
Scheu, S. et al. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin β in mesenteric lymph node genesis. J. Exp. Med. 195, 1613–1624 (2002).
Pasparakis, M. et al. Peyer's patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor. Proc. Natl Acad. Sci. USA 94, 6319–6323 (1997).
Pasparakis, M., Alexopoulou, L., Episkopou, V. & Kollias, G. Immune and inflammatory responses in TNFα-deficient mice: a critical requirement for TNFα in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184, 1397–1411 (1996).
Körner, H. et al. Distinct role for lymphotoxin-α and tumor necrosis factor in organogenesis and spatial organization of lymphoid tissue. Eur. J. Immunol. 27, 2600–2609 (1997).
Pfeffer, K. et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).
Erickson, S. L. et al. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature 372, 560–563 (1994).
Koike, R. et al. The splenic marginal zone is absent in alymphoplastic aly mutant mice. Eur. J. Immunol. 26, 669–675 (1996).
Matsumoto, M. et al. Involvement of distinct cellular compartments in the abnormal lymphoid organogenesis in lymphotoxin-α-deficient mice and alymphoplasia (aly) mice defined by the chimeric analysis. J. Immunol. 163, 1584–1591 (1999).
Shinkura, R. et al. Alymphoplasia is caused by a point mutation in the mouse gene encoding NF-κB-inducing kinase. Nature Genet. 22, 74–77 (1999).
Yamada, T. et al. Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-κB-inducing kinase. J. Immunol. 165, 804–812 (2000).
Weih, F. & Caamano, J. Regulation of secondary lymphoid organ development by the nuclear factor-κB signal transduction pathway. Immunol. Rev. 195, 91–105 (2003).
Cariappa, A., Liou, H. C., Horwitz, B. H. & Pillai, S. Nuclear factor κB is required for the development of marginal zone B lymphocytes. J. Exp. Med. 192, 1175–1182 (2000).
Franzoso, G. et al. Mice deficient in nuclear factor (NF)-κB/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J. Exp. Med. 187, 147–159 (1998).
Poljak, L., Carlson, L., Cunningham, K., Kosco-Vilbois, M. H. & Siebenlist, U. Distinct activities of p52/NF-κB required for proper secondary lymphoid organ microarchitecture: functions enhanced by Bcl-3. J. Immunol. 163, 6581–6588 (1999).
Weih, D., Yilmaz, Z. & Weih, F. Essential role of RelB in germinal center and marginal zone formation and proper expression of homing chemokines. J. Immunol. 167, 1909–1919 (2001).
Franzoso, G. et al. Critical roles for the Bcl-3 oncoprotein in T cell-mediated immunity, splenic microarchitecture, and germinal center reactions. Immunity 6, 479–490 (1997).
Pabst, O., Förster, R., Lipp, M., Engel, H. & Arnold, H. H. NKX2.3 is required for MAdCAM-1 expression and homing of lymphocytes in spleen and mucosa-associated lymphoid tissue. EMBO J. 19, 2015–2023 (2000).
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We thank all of our collaborators, particularly B. Steiniger, for helpful discussions.
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Glossary
- VENOUS SINUSOIDAL SYSTEM
-
Blood sinuses in which the blood is collected from the cords in the splenic red pulp and transported to the efferent vein of the spleen (the vena lienalis). The structure of the wall of the sinuses allows the removal of ageing erythrocytes from the circulation.
- TRABECULA
-
A bar of connective tissue that protrudes from the capsule into the splenic tissue. Together, the capsule and the trabeculae form a supporting, three-dimensional framework that provides some rigidity to the spleen.
- PATTERN-RECOGNITION RECEPTOR
-
A receptor that recognizes unique structures that are present at the surface of microorganisms. Signalling through these receptors leads to the production of pro-inflammatory cytokines and chemokines and to the expression of co-stimulatory molecules by antigen-presenting cells. The expression of co-stimulatory molecules, together with the presentation of antigenic peptides, by antigen-presenting cells couples innate immune recognition of pathogens with the activation of adaptive immune responses.
- VENA LIENALIS
-
The efferent vein of the spleen.
- PHAGOLYSOSOME
-
An intracellular vesicle that results from the fusion of phagosomes, which enclose extracellular material that has been ingested, and lysosomes, which contain lytic enzymes.
- HAPTOGLOBIN
-
A plasma protein that can bind free haemoglobin in the bloodstream.
- SIDEROPHORE
-
A compound that is secreted by microorganisms that efficiently bind iron.
- TOLL-LIKE RECEPTOR
-
A type of pattern-recognition receptor that is expressed by macrophages and dendritic cells. These receptors recognize unique structures that are present at the surface of microorganisms.
- PLASMABLAST
-
An activated B cell at an intermediate stage of differentiation. Plasmablasts leave germinal centres and migrate through the lymph and the blood to distant sites, such as the skin and the lamina propria of the intestines, to become antibody-producing plasma cells.
- PLASMA CELL
-
A terminally differentiated cell of the B-cell lineage that secretes large amounts of antibodies.
- RADIATION CHIMERA
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An animal that contains cell populations of different genotypes as a result of the transfer of haematopoietic stem cells from fetal liver or bone marrow to a recipient in which haematopoietic-cell populations (and other actively dividing cell populations) have been fully or partially destroyed by lethal or sub-lethal ionizing radiation.
- FOLLICULAR DENDRITIC CELL (FDC).
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A stromal cell that is crucial for the development of germinal centres in B-cell follicles. The interaction between FDCs and B cells is thought to be essential for isotype switching and somatic hypermutation.
- MARGINAL-ZONE MACROPHAGE
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A large macrophage in the splenic marginal zone that is characterized by the expression of a unique set of pattern-recognition receptors.
- MARGINAL-ZONE METALLOPHILIC MACROPHAGE
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A macrophage that is located at the border of the white pulp and the marginal zone of the spleen. The precise function of these cells at this site is not known.
- LYMPHOID-TISSUE INDUCER CELL
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A cell that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue (NALT). Lymphoid-tissue inducer cells are required for the development of these lymphoid organs. The inductive capacity of these cells for the generation of Peyer's patches and NALT has been shown by adoptive transfer, and it is generally assumed that they have a similar function in the formation of lymph nodes.
- HIGH ENDOTHELIAL VENULE (HEV).
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A specialized venule that occurs in secondary lymphoid organs, except the spleen. HEVs allow continuous transmigration of lymphocytes as a consequence of the constitutive expression of adhesion molecules and chemokines at their luminal surface.
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Mebius, R., Kraal, G. Structure and function of the spleen. Nat Rev Immunol 5, 606–616 (2005). https://doi.org/10.1038/nri1669
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DOI: https://doi.org/10.1038/nri1669
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