Casitas-B-lineage lymphoma protein-b (Cbl-b) is an adaptor protein and RING finger domain-type E3 ubiquitin (Ub) ligase, and has been shown to be important for the maintenance of a balance between immunity and tolerance. Previously, we demonstrated that CD28 costimulation potentiates TCR-induced Cbl-b ubiquitination and degradation, whereas CTLA-4-B7 interaction is required for Cbl-b re-expression. These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation and tolerance. In strong support of this notion, Cbl-b-/- T cells are resistant to anergy induction in vitro and in vivo. Indeed, Cbl-b-/- mice are highly susceptible to autoimmunity. Further studies reveal that Cbl-b not only down- regulates T cell activation, but also selectively inhibits T helper 2 (Th2) differentiation and allergic airway inflammation. Intriguingly, Cbl-b favors peripheral conversion of naove CD4? T cells into CD4???? Tregs (iTregs) in vitro. Although Cbl-b-/- CD4? naturally-occurring Tregs (nTregs) display normal suppressive activity in vitro, Cbl-b-/- CD4? effector T cells (Teffs) are resistant to regulation by nTregs which is possibly due to increased production of IL-4. At the molecular levels, Cbl-b selectively associates with Stat-6, an important transcription factor involved in Th2 cell differentiation, upon IL-4 ligation and may inhibit Th2 differentiation by targeting Stat-6 for degradation. These processes are heightened in the TCR signaling. Furthermore, Cbl-b facilitates iTreg generation by inhibiting PI3-K/Akt activation. Based upon the above data, we hypothesize that Cbl-b targets Stat-6 for ubiquitination and facilitate iTreg generation, thus inhibiting Th2 responses and allergic airway inflammation. To test this hypothesis, we will investigate: 1) whether Cbl-b inhibits Th2 responses by targeting Stat-6 for ubiquitination, thus suppressing alleric airway inflammation;and 2) whether and how Cbl-b regulates the development of iTregs in vivo, therefore modulating Th2 responses and allergic airway inflammation.
The specific aims of this proposal will address fundamental question: how does Cbl-b regulate its target substrates/pathways related to its biological functions. A better understanding of cellular and molecular mechanisms of Cbl-b biological functions may lead to potential therapeutic approaches for autoimmune diseases and allergic asthma.

Public Health Relevance

Cbl-b is an E3 ubiquitin ligase which is responsible for targeting unwanted proteins for degradation, and hence prevents the accumulation of these unwanted proteins. Mice lacking Cbl-b display hyper-activity of their T and B lymphocytes and are highly susceptible to autoimmunity and asthma induction. We are interested in further characterizing whether and how Cbl-b regulates its substrate proteins affecting its biological functions including T helper 2 cell differentiation and regulatory T cell development which tune the susceptibility to asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI090901-08
Application #
8290435
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Davidson, Wendy F
Project Start
2003-03-01
Project End
2012-08-31
Budget Start
2012-07-01
Budget End
2012-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$168,280
Indirect Cost
$60,408
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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