Transforming growth factor-beta1 (TGF-beta1) is a potent suppressive cytokine with an essential role in immune homeostasis. TGF-beta1 can be produced by and can act on virtually all lineages of leukocytes. My preliminary studies show that T cells are the central targets of TGF-beta1, as mice with a T cell-specific deletion of TGF-beta receptor develop severe immunopathology. My long-term goal is therefore to decipher the molecular and cellular T cell tolerance mechanisms elicited by TGF-beta1 and apply them to the study of collagen-induced arthritis. To gain a better understanding of the molecular mechanisms, I have performed large-scale gene expression profile studies and identified new target genes involved in TGF-beta1 regulation of effector T cell differentiation. I have also developed unique mouse models for the study of the cellular T cell tolerance mechanisms. To identify cells that express TGF-beta1,1 have engineered a GFP reporter mouse strain, and have found that dendritic cells (DCs) and T cells express high levels of TGF-beta1. To investigate the cell type-specific function of TGF-beta1, I have generated a strain of TGF-beta1 conditional knockout mice. T cell-specific deletion of TGF-beta1 results in a chronic inflammatory disease, emphasizing the importance of T cell-produced TGF-beta1 in T cell tolerance. Based on these data, I hypothesize that TGF-beta1 essentially regulates peripheral T cell tolerance by targeting the T cell differentiation program; T cell-produced TGF-beta1 synergizes with DC-produced TGF-beta1 to ensure T cell tolerance in vivo; and these tolerance pathways are important regulators of collagen-induced arthritis. ? ? To further address these hypotheses, I plan the following specific aims:
Aim 1. To define the molecular mechanisms by which TGF-beta1 regulates effector T cell differentiation.
Aim 2. To determine the cellular mechanisms by which TGF-beta1 regulates T cell responses.
Aim 3. To study the function of TGF-beta1 produced by T cells and dendritic cells in the regulation of collagen-induced arthritis. ? ? TGF-beta1 is an important molecule for immune cell functions. My goal is to study the mechanism by which TGF-beta1 regulates T lymphocyte activity and the development of arthritis. ? ? ? ?
