Abstract
Lymphotoxin-β receptor (LTβR) axis plays a crucial role in development and compartmentalization of peripheral lymphatic organs. But, it is also required for the appropriate function and maintenance of structural integrity of the thymus: in LTβR-deficient animals the clonal deletion of autoreactive lymphocytes is impaired and differentiation of thymic medullary epithelial cells is disturbed. In this study, using several markers, we showed that thymic metallophilic macrophages were lacking in LTβR-deficient mice. In tumor necrosis factor receptor-I (p55)-deficient mice (which we used as positive control) thymic metallophilic cells were located, similarly as in normal mice, in the thymic cortico-medullary zone at the junction of cortex and medulla. These findings show that LTβR is necessary for maintenance of metallophilic macrophages in the thymus and provide further evidence that these cells may represent a factor involved in thymic negative selection.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anderson G, Owen JJT, Moore NC, Jenkinson EJ (1994) Thymic epithelial cells provide unique signals for positive selection of CD4+ or CD8+ thymocytes in vitro. J Exp Med 179:2027–2031
Bancroft JD, Stevens A (1982) Theory and practice of histological techniques, 2nd edn. Churchill Livingstone, Edinburgh
Boehm T, Scheu S, Pfeffer K, Bleul CC (2003) Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTβR. J Exp Med 198:757–769
Chen JW, Pan W, D‘Souza MP, August JT (1985) Lysosome-associated membrane proteins: characterization of LAMP-1 of macrophage P388 and mouse embryo 3T3 cultured cells. Arch Biochem Biophys 239:574–586
Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA, Peterson P, Wang Y, Ware C, Fu YX (2003) Lymphotoxin pathway directs thymic Aire expression. Nat Immunol 4:1121–1127
Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039
Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, Peltonen L, Walter J, Kyewski B (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202:33–45
Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K (1998) The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59–70
Hogquist KA, Baldwin TA, Jameson SC (2005) Central tolerance: learning self-control in the thymus. Nat Rev Immunol 5:772–782
Jenkins MK, Schwartz RH, Pardoll DM (1988) Effects of cyclosporine A on T cell development and clonal deletion. Science 241:1655–1658
Jenkinson EJ, Anderson G, Owen JJT (1992) Studies on T-cell maturation on defined thymic stromal cells in vitro. J Exp Med 176:845–853
Kabashima K, Banks TA, Mark Ansel K, Lu TT, Ware CF, Cyster JG (2005) Intrinsic lymphotoxin-β receptor requirement for homeostasis of lymphoid tissue dendritic cells. Immunity 22:439–450
Kraal G, Janse M (1986) Marginal metallophilic cells of the mouse spleen identified by a monoclonal antibody. Immunology 58:665–669
Leder LD, Stutte HJ (1975) Seminar for hematologic-cytochemical techniques. Verh Dtsch Ges Pathol 59:503–509
Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC (2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4:350–354
Liston A, Gray DH, Lesage S, Fletcher AL, Wilson J, Webster KE, Scott HS, Boyd RL, Peltonen L, Goodnow CC (2004) Gene dosage-limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J Exp Med 200:1015–1026
Martinez-Pomares L, Kosco-Vilbois M, Darley E, Tree P, Herren S, Bonnefoy JY, Gordon S (1996) Fc chimeric protein containing the cysteine-rich domain of the murine mannose receptor binds to macrophages from splenic marginal zone and lymph node subcapsular sinus and to germinal centers. J Exp Med 184:1927–1937
Matsumoto M, Fu YX, Molina H, Chaplin DD (1997) Lymphotoxin-alpha-deficient and TNF receptor-I-deficient mice define developmental and functional characteristics of germinal centers. Immunol Rev 156:137–144
Milićević NM, Milićević Ž (1984) Enzyme-histochemical characterization of macrophages in the rat thymus, with special reference to metallophilic cells of the cortico-medullary zone. J Leukoc Biol 36:761–769
Milićević NM, Milićević Ž (1985) Naphthol AS D chloroacetate esterase-positive macrophages in the cortico-medullary zone of the normal rat thymus. Virchows Arch B Cell Pathol Incl Mol Pathol 50:193–198
Milićević NM, Milićević Ž (1989) Histochemistry of the acutely involuted thymus in nickel chloride-treated rats. J Comp Pathol 101:143–150
Milićević NM, Milićević Ž (1998) Cyclosporin A-induced changes of the thymic microenvironment. A review of morphological studies. Histol Histopathol 13:1183–1196
Milićević NM, Milićević Ž (2000) Ultrastructural identification of specialized endocytic compartments in macrophages of thymic cortico-medullary zone and germinal centers of peripheral lymphatic organs of the rat. Ann Anat 182:471–478
Milićević NM, Milićević Ž (2004) Thymus cell–cell interactions. Int Rev Cytol 235:1–52
Milićević NM, Milićević Ž, Piletić O, Mujović S, Ninkov V (1983) Reactivity of thymic metallophilic cells during the regeneration after the application of cyclophosphamide. J Reticuloendothel Soc 34:501–507
Milićević NM, Milićević Ž, Piletić O, Mujović S, Ninkov V (1985) Metallophilic and PAS-positive cells of the rat thymus. Topographical distribution and histological properties after the application of cyclophosphamide. Anat Histol Embryol 14:359–364
Milićević NM, Milićević Ž, Čolić M, Mujović S (1987) Ultrastructural study of macrophages in the rat thymus, with special reference to the cortico-medullary zone. J Anat 150:89–98
Milićević NM, Milićević Ž, Čolić M (1989) Macrophages of the rat thymus after cyclosporine treatment: histochemical, enzymehistochemical and immunohistochemical study. Virchows Arch B Cell Pathol Incl Mol Pathol 57:237–244
Sprent J, Kishimoto H (2002) The thymus and negative selection. Immunol Rev 185:126–135
Villasenor J, Benoist C, Mathis D (2005) AIRE and APECED: molecular insights into an autoimmune disease. Immunol Rev 204:156–164
Wang YG, Kim KD, Wang J, Yu P, Fu YX (2005) Stimulating lymphotoxin beta receptor on the dendritic cells is critical for their homeostasis and expansion. J Immunol 175:6997–7002
Yu P, Wang Y, Chin RK, Martinez-Pomares L, Gordon S, Kosco-Vibois MH, Cyster J, Fu YX (2002) 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
Acknowledgments
Thanks are due to Lidija Gutjahr for technical assistance. This work was supported by Deutsche Forschungsgemeinschaft (We 1175/4-3) and the grant of the Ministry for Science and Protection of Natural Environment of Republic of Serbia (no. 145016). Novica M. Milićević was a fellow of the Alexander von Humboldt-Foundation, Bonn, Germany.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Milićević, N.M., Nohroudi, K., Labudović-Borović, M. et al. Metallophilic macrophages are lacking in the thymus of lymphotoxin-β receptor-deficient mice. Histochem Cell Biol 126, 687–693 (2006). https://doi.org/10.1007/s00418-006-0202-5
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00418-006-0202-5