The goal of this project is to identify mechanisms mediating effects of endogenous TGF-beta1 on the development and function of specific hematopoietic cell lineages. Experimental evidence from in vitro studies of function suggest a critical role for TGF-beta1 in regulating myelopoiesis and immune cell function, but such studies are limited by their inability to reproduce the complex in vivo network which ordinarily influences the genesis and function of these cell populations. Our approach to this problem has been to utilize the TGF-beta1(-/-) mouse as the basis for establishing complimentary in vivo model systems; each system designed to isolate TGF-beta1-deficiency in a distinct background. This approach has enabled us to identify critical links between cell cycle control by TGF-beta1, immune cell maturation and function, and hematopoietic cell growth and differentiation, as they occur in vivo. Examples include our demonstration of myeloid hyperplasia as a distinct phenotype in TGF-beta1(-/-) mice, and recognition that altered expression of several regulators of the cell cycle may be critical in the establishment of the autoimmune process which evolves in the absence of endogenous TGF-beta1 expression. Through adoptive transfer studies, including bone marrow transplant experiments and studies of thymic and splenic reconstitution in nude mice, we have also identified novel autocrine effects of TGF-beta1 and their role in the autoimmune and hematopoietic manifestations of TGF-beta1-deficiency. We have also determined that TGF-beta1-deficient animals lack epidermal Langerhans cells (LC) and gp40 positive dendritic cells (DC) in lymph nodes, suggesting that lymphoid DC as well as LC are perturbed.
We aim to study DC populations in TGF-beta1(-/-) mice, including MHC-II(-/-) and athymic nude strains developed in our lab, and to determine precise mechanisms by which TGF-beta1 regulates DC ontogeny. Our current and future research aims to define both the cellular and molecular mechanisms which mediate these effects, particularly those which govern cell cycle progression and the growth inhibitory responses to TGF-beta.
| Mamura, Mizuko; Lee, WoonKyu; Sullivan, Timothy J et al. (2004) CD28 disruption exacerbates inflammation in Tgf-beta1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-beta1. Blood 103:4594-601 |
| Wolfraim, Lawrence A; Fernandez, Tania M; Mamura, Mizuko et al. (2004) Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med 351:552-9 |
| Kim, S-J; Letterio, J (2003) Transforming growth factor-beta signaling in normal and malignant hematopoiesis. Leukemia 17:1731-7 |
| Cao, Zhouhong; Flanders, Kathleen C; Bertolette, Daniel et al. (2003) Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. Blood 101:498-507 |
