Scientific Abstract

Proposal No.  IBD-0025
Principal Investigator: Luk Van Parijs, Ph.D.
Applicant Organization: Massachusetts Institute of Technology (Cambridge, U.S.A.)
Project Title:  Control of regulatory T cell activity and inflammatory bowel disease by interleukin-2
Period of Award:  October 1, 2002 - September 30, 2003

CD25, the alpha chain of the IL-2 receptor (IL-2Ra), defines a population of CD4+ T cells that has the capacity to suppress the proliferation of pathogenic T cells and block the development of inflammatory bowel disease (IBD).  These cells are referred to as regulatory T cells (T reg).  Because of their potent inhibitory effect on immune-mediated diseases, these cells have been the focus of much recent interest, both from a basic science and a clinical perspective.

The constitutive expression of CD25/IL-2Ra chain, as well as the other components of the IL-2 receptor, namely the IL-2Rb and IL-2Rg chains, on T regs suggests that IL-2 is an important cytokine for these cells.  Supporting this idea, IL-2-, IL-2Ra-, and IL-2Rb-deficient mice develop inflammatory bowel disease in the presence of normal enteric flora, as well as an autoimmune syndrome that is characterized by the accumulation of activated CD4+ T cells in the spleen and lymph nodes and the production of autoantibodies.  Consistent with a defect in the T reg compartment, we and others have shown that mice that are deficient in IL-2 have reduced numbers of CD25+CD4+ T cells.  Our recent results suggest that this cytokine is required for the differentiation and maintenance of T regs.

We now propose to examine how IL-2 signals promote T reg activity and prevent the development of IBD.  In order to accomplish this, we have established an adoptive transfer model of IBD in the mouse.  We will use this model system to test the activity of T regs that are deficient in specific IL-2 signaling molecules.  This will allow us to identify IL-2 signals that are necessary for T regs to prevent IBD.  We will then test whether we can rescue the activity of IL-2-deficient T regs by inducing specific IL-2 signals using a novel lentivirus-based gene transfer system.  We will also examine the role that IL-2 plays in maintaining T regs in vivo by transferring wild type and mutant T regs into lymphopenic hosts.  Finally, we will perform a more open-ended search for genes that are induced by IL-2 in T regs by comparing gene expression profiles in wild type and IL-2-deficient T regs, as well as in T regs derived from IL-2-deficient mice that have been treated with IL-2 in vivo.  Our studies should provide important insights into the biology of T regs and how they prevent IBD.  The studies will also identify new targets for therapies aimed at preventing or curing this disease.