Title

The E3 ubiquitin ligase Cbl-b and the nuclear hormone receptor PPARgamma: Balancing immunoregulation and autoimmunity

Date of Completion

January 2007

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Mice deficient in the E3 ubiquitin ligase Cbl-b (Cbl-b-/-mice) have signaling defects that result in CD28-independent T cell activation, increased IL-2 production, hyper-reactive T cells and autoimmunity. While CD4+CD25+ regulatory T cells (Tregs) play a critical role in preventing autoimmunity, the status of Cbl-b-/- Tregs has not been examined. We have now found that while Cbl-b-/-Tregs exhibit normal regulatory function, Cbl-b -/-CD4+CD25- T effector cells (Teff) are "resistant to regulation" in that they are not inhibited by either Cbl-b-/- or wild-type Tregs. In addition, Cbl-b-/- Teff also demonstrate in-vitro and in in-vivo resistance to the regulatory cytokine TGF-β. Overall, these studies are the first to document that Cbl-b plays an integral role in Teff sensitivity to both Treg and TGF-β-mediated suppression and that its absence results in multifunctional, disease-related, immunoregulatory defects. Based on commonalities in our model and in other recently described models of resistance to regulation, we postulate that the PI3K-Akt pathway is a primary determinant of Teff sensitivity to Treg and TGF-β-mediated suppression. ^ To further understand Teff-Treg interactions, we next asked whether a newly identified approach for treating autoimmunity might mechanistically work by enhancing Treg function. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism but PPARγ ligands have recently been found to also down-regulate most immune system cells including APCs and pathogenic T cells. While these effects putatively underlie the efficacy of PPARγ ligands in treating animal models of autoimmunity, no studies have examined the role of Tregs in mediating the immunoregulatory effects of PPARγ ligands. We have now found that the PPARγ ligand ciglitazone significantly enhances the in-vitro generation of iTregs. Surprisingly, and contrary to the current paradigm, we have also found that the in-vivo immunotherapeutic effect of ciglitazone requires the presence of nTregs. Finally, we present evidence that PPARγ, even in the absence of exogenous ligands, plays an integral role in the normal functioning of Tregs. Overall, these studies have identified novel effects of Cbl-b and PPARγ on Teff-Treg interactions and may shed light on both the cause and treatment of autoirnmune diseases. ^