The development of autoimmunity involves the failure of the mechanisms that regulate the ability to discriminate self from non-self. The primary means of regulating self-tolerance is through the deletion of self- reactive cells in the thymus. However, this mechanism is not perfect and auto-reactive clones do escape into the periphery. Peripheral tolerance is generated through a variety of mechanisms including T cell anergy and T cell indifference or ignorance. Recently, another more active mechanism of tolerance induction has been identified that is controlled by a population of regulatory T cells which actively suppress the function of auto- reactive T cells. These T cells, known as Treg cells, play a critica role in preventing responses to self-antigens as fatal autoimmunity develops in their absence. However, the mechanism by which these cells perform their tasks is as yet unclear. Recent work has shown that the forkhead/winged-helix protein FOXP3 is expressed predominantly in Treg cells and is both necessary and sufficient for their development and function. FOXP3 acts as a transcriptional regulator, targeting cytokine genes whose expression is induced in stimulated CD4+ T cells. We have identified additional proteins that interact with FOXP3 and regulate its function. One of these, referred to FIK (FOXP3 Interacting KRAB domain protein), is found in human but not murine Tregs and arises as a consequence of Treg-specific alternative splicing of the mRNA encoding human ZFP90. FIK in turn interacts with KAP1, an adaptor linking FOXP3 to a repressive chromatin remodeling complex. We have preliminary data showing that disruption of these complex results in loss of Treg suppressor function and expression of genes otherwise repressed in Tregs. The experiments in this proposal will address: 1. The role of the FOXP3-FIK-KAP1 complex in regulating gene expression in human Tregs, and 2. The role of the FOXP3-FIK-KAP1 complex in regulating human Treg function.
Identification and characterization of the factors that control the ability of the immune system to distinguish self from non-self is critical to the development o therapeutics for the treatment of autoimmune diseases. A population of T cells referred to as regulatory T cells, or Tregs, is responsible for regulating immune responses to self. The transcription factor FOXP3 has been found to be essential for their development and function, and the loss of FOXP3 leads to fatal autoimmunity in humans and mice. Thus, a better understanding of the mechanism by which FOXP3 controls Treg function will provide insight into Treg biology and identify potential targets for manipulation of this important T cell subset.
