Reconstitution of Lethally Irradiated Adult Mice with Dominant Negative TGF-{beta} Type II Receptor-Transduced Bone Marrow Leads to Myeloid Expansion and Inflammatory Disease

• Published in: The Journal of immunology (1950) 2002-10, Vol.169 (7), p.3485-3491
• Main Authors: Shah, Ali H, Tabayoyong, William B, Kimm, Simon Y, Kim, Seong-Jin, van Parijs, Luk, Lee, Chung
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

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-[beta]1-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].