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Type II Receptor-Transduced Bone Marrow Leads to Myeloid Expansion and Inflammatory Disease1
* Department of Urology, Northwestern University Medical School, Chicago, IL 60611;
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892; and
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
TGF-
regulation of immune homeostasis has been investigated in
the context of cytokine knockout (TGF- null) mice, in which
particular TGF- 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- have not been addressed in
the context of an in vivo mouse model in which multi-isoform TGF-
signaling is abrogated in multiple leukocyte lineages while leaving
nonhemopoietic tissue unaffected. Here we report the development of a
murine model of TGF- insensitivity limited to the hemopoietic tissue
of adult wild-type C57BL/6 mice based on retroviral-mediated gene
transfer of a dominant negative TGF- type II receptor targeting
murine bone marrow. Unlike the lymphoproliferative syndrome observed in
TGF-1-deficient mice, the disruption of TGF- 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- acts as
a negative regulator of immune function, but that lack of functional
TGF- signaling in the myeloid compartment of adult mice may trigger
suppression of lymphocytes, which would otherwise proliferate when
rendered insensitive to TGF-.
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