title: Reconstitution of lethally irradiated adult mice with dominant negative TGF-beta type II receptor-transduced bone marrow leads to myeloid expansion and inflammatory disease.
abstract: TGF-beta regulation of immune homeostasis has been investigated in the context of cytokine knockout (TGF-beta null) mice, in which particular TGF-beta isoforms are disrupted throughout the entire organism, as well as in B and T cell-specific transgenic models, but to date the immunoregulatory effects of TGF-beta have not been addressed in the context of an in vivo mouse model in which multi-isoform TGF-beta signaling is abrogated in multiple leukocyte lineages while leaving nonhemopoietic tissue unaffected. Here we report the development of a murine model of TGF-beta insensitivity limited to the hemopoietic tissue of adult wild-type C57BL/6 mice based on retroviral-mediated gene transfer of a dominant negative TGF-beta type II receptor targeting murine bone marrow. Unlike the lymphoproliferative syndrome observed in TGF-beta1-deficient mice, the disruption of TGF-beta signaling in bone marrow-derived cells leads to dramatic expansion of myeloid cells, primarily monocytes/macrophages, and is associated with cachexia and mortality in lethally irradiated mice reconstituted with dominant negative receptor-transduced bone marrow. Surprisingly, there was a notable absence of T cell expansion in affected animals despite the observed differentiation of most cells in the T cell compartment to a memory phenotype. These results indicate not only that TGF-beta acts as a negative regulator of immune function, but that lack of functional TGF-beta signaling in the myeloid compartment of adult mice may trigger suppression of lymphocytes, which would otherwise proliferate when rendered insensitive to TGF-beta.
authors.affiliation: Department of Urology, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Shah
authors.forename: William B
authors.initials: WB
authors.lastname: Tabayoyong
authors.forename: Simon Y
authors.initials: SY
authors.lastname: Kimm
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Luk
authors.initials: L
authors.lastname: Van Parijs
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002100:Cachexia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000032:analysis / Q000138:chemical synthesis / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000821:virology; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019041:L-Selectin / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage* / Q000235:genetics* / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic; D019076:Transgenes / Q000276:immunology
chemical_list: D018960:Hyaluronan Receptors; D015375:Receptors, Interleukin-2; D018125:Receptors, Transforming Growth Factor beta; D019041:L-Selectin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II