Research Abstracts Online
January 2009 - March 2010
University of Minnesota Twin Cities
Department of Medicine
PI: Alexander Khoruts
Translational Control of Foxp3+ Regulatory T Cell Induction
Peripheral induction of antigen-specific Foxp3+ CD4 T cells, or regulatory T cells (Tregs), is a potential pathway to treat autoimmune diseases. It is also an undesirable outcome of the immune response, which limits recovery from chronic infections and malignancies. Early work has shown that Treg induction is favored by suboptimal or low-dose antigen stimulation. More recently, these researchers and others have demonstrated that mTOR blockade during antigen activation favors peripheral Treg induction. Similarly, other means of cellular metabolic stress during antigen activation, e.g., L-tryptophan deprivation, also lead to induction of anergic and Treg phenotypes. One common feature of these examples is inhibition of cap-dependent mRNA translation. Of course, it is well recognized that a small fraction of genes can actually increase their expression in times of metabolic stress by utilizing alternative mechanisms of translation initiation.
The central hypothesis of this proposal is that translational control of gene expression plays a critical role in early stages of Treg phenotype induction. The researchers have performed preliminary experiments and are now performing genome-wide translational profiling to identify additional candidate molecules that are involved in driving Treg induction.This mechanism of Treg induction represents a new paradigm in the field, which will complement other current models that focus primarily on chromatin remodeling in T cell differentiation. Increased mechanistic understanding of Treg induction is critical to future development of new therapeutic strategies in treatment of a great variety of diseases ranging from autoimmunity to cancer.
Johnthomas Kang, Research Associate