title: LTbetaR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen.
abstract: The formation of lymph nodes is a complex process crucially controlled through triggering of LTbetaR on mesenchymal cells by LTalpha(1)beta(2) expressing lymphoid tissue inducer (LTi) cells. This leads to the induction of chemokines to attract more hematopoietic cells and adhesion molecules to retain them. In this study, we show that the extravasation of the first hematopoietic cells at future lymph node locations occurs independently of LTalpha and that these cells, expressing TNF-related activation-induced cytokine (TRANCE), are the earliest LTi cells. By paracrine signaling the first expression of LTalpha(1)beta(2) is induced. Subsequent LTbetaR triggering on mesenchymal cells leads to their differentiation to stromal organizers, which now also start to express TRANCE, IL-7, as well as VEGF-C, in addition to the induced adhesion molecules and chemokines. Both TRANCE and IL-7 will further induce the expression of LTalpha(1)beta(2) on newly arrived immature LTi cells, resulting in more LTbetaR triggering, generating a positive feedback loop. Thus, LTbetaR triggering by LTi cells during lymph node development creates a local environment to which hematopoietic precursors are attracted and where they locally differentiate into fully mature, LTalpha(1)beta(2) expressing, LTi cells. Furthermore, the same signals may regulate lymphangiogenesis to the lymph node through induction of VEGF-C.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU (Vrije Universiteit) University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Vondenhoff
authors.forename: Mascha
authors.initials: M
authors.lastname: Greuter
authors.forename: Gera
authors.initials: G
authors.lastname: Goverse
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.forename: Pieter
authors.initials: P
authors.lastname: Dewint
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Kerim
authors.initials: K
authors.lastname: Hoorweg
authors.forename: Georg
authors.initials: G
authors.lastname: Kraal
authors.forename: Reina E
authors.initials: RE
authors.lastname: Mebius
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000196:embryology / Q000276:immunology* / Q000378:metabolism; D008221:Lymphoid Tissue / Q000196:embryology / Q000276:immunology / Q000378:metabolism; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053259:Lymphotoxin beta Receptor / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D042501:Angiogenic Proteins; D016207:Cytokines; C505699:Ltbr protein, mouse; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse