PMID:12421925

Citation	Hager-Theodorides, AL, Outram, SV, Shah, DK, Sacedon, R, Shrimpton, RE, Vicente, A, Varas, A and Crompton, T (2002) Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation. J. Immunol. 169:5496-504
Abstract	Bone morphogenetic protein (BMP)2 and BMP4 are involved in the development of many tissues. In this study, we show that BMP2/4 signaling is involved in thymocyte development. Our data suggest that termination of BMP2/4 signaling is necessary for differentiation of CD44(+)CD25(-)CD4(-)CD8(-) double negative (DN) cells along the T cell lineage. BMP2 and BMP4 are produced by the thymic stroma and the requisite BMP receptor molecules (BMPR-1A, BMPR-1B, BMPR-II), and signal transduction molecules (Smad-1, -5, -8, and -4) are expressed by DN thymocytes. BMP4 inhibits thymocyte proliferation, enhances thymocyte survival, and arrests thymocyte differentiation at the CD44(+)CD25(-) DN stage, before T cell lineage commitment. Neutralization of endogenous BMP2 and BMP4 by treatment with the antagonist Noggin promotes and accelerates thymocyte differentiation, increasing the expression of CD2 and the proportion of CD44(-)CD25(-) DN cells and CD4(+)CD8(+) double-positive cells. Our study suggests that the BMP2/4 pathway may function in thymic homeostasis by regulating T cell lineage commitment and differentiation.
Links	PubMed
Keywords	Activin Receptors, Type I/biosynthesis; Activin Receptors, Type I/genetics; Adjuvants, Immunologic/pharmacology; Adjuvants, Immunologic/physiology; Animals; Antigens, CD44/biosynthesis; Antigens, CD44/metabolism; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins/antagonists & inhibitors; Bone Morphogenetic Proteins/physiology; Carrier Proteins; Cell Differentiation/genetics; Cell Differentiation/immunology; Cell Survival/genetics; Cell Survival/immunology; Cells, Cultured; Dose-Response Relationship, Immunologic; Fetus; Gene Expression Regulation/immunology; Genes, T-Cell Receptor beta/genetics; Genes, T-Cell Receptor delta/genetics; Growth Inhibitors/physiology; Mice; Mice, Inbred BALB C; Mice, Knockout; Organ Culture Techniques; Protein-Serine-Threonine Kinases; Proteins/pharmacology; Receptors, Growth Factor; Receptors, Interleukin-2/biosynthesis; Receptors, Interleukin-2/metabolism; Recombinant Fusion Proteins/pharmacology; Signal Transduction/genetics; Signal Transduction/immunology; T-Lymphocytes/cytology; T-Lymphocytes/metabolism; Thymus Gland/cytology; Thymus Gland/metabolism; Transforming Growth Factor beta
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