Reconstitution of lethally irradiated adult mice with dominant negative TGF-β type II receptor-transduced bone marrow leads to myeloid expansion and inflammatory disease

Ali H. Shah, William B. Tabayoyong, Simon Y. Kimm, Seong Jin Kim, Luk Van Parijs, Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

TGF-β regulation of immune homeostasis has been investigated in the context of cytokine knockout (TGF-β null) mice, in which particular TGF-β 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-β have not been addressed in the context of an in vivo mouse model in which multi-isoform TGF-β signaling is abrogated in multiple leukocyte lineages while leaving nonhemopoietic tissue unaffected. Here we report the development of a murine model of TGF-β insensitivity limited to the hemopoietic tissue of adult wild-type C57BL/6 mice based on retroviral-mediated gene transfer of a dominant negative TGF-β type II receptor targeting murine bone marrow. Unlike the lymphoproliferative syndrome observed in TGF-β1-deficient mice, the disruption of TGF-β 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-β acts as a negative regulator of immune function, but that lack of functional TGF-β signaling in the myeloid compartment of adult mice may trigger suppression of lymphocytes, which would otherwise proliferate when rendered insensitive to TGF-β.

Original languageEnglish (US)
Pages (from-to)3485-3491
Number of pages7
JournalJournal of Immunology
Volume169
Issue number7
DOIs
StatePublished - Oct 1 2002

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Reconstitution of lethally irradiated adult mice with dominant negative TGF-β type II receptor-transduced bone marrow leads to myeloid expansion and inflammatory disease'. Together they form a unique fingerprint.

  • Cite this