The goal of this exploratory proposal is to study the role of TGF?R3, also known as betaglycan, in T-cell development and immune responses. Although TGF?R3 is broadly expressed in cells of both the innate and adaptive immune system, very little is known about its function in immunity. Loss of expression of TGF?R3 in several cancers is associated with poor prognosis. We have recently reported that TGF?R3 expression in thymocytes is developmentally regulated, and interruption of its signaling leads to inhibition o T-cell maturation. TGF?R3-null mice exhibit embryonic lethality which has hampered studies to determine its function in the immune system. We have developed a novel conditional TGF?R3fl/fl mouse that offers the opportunity to selectively target the inactivation of TGF?R3 in tissues of choice. We show that induced inactivation of TGF?R3 in the adult mouse leads to profound changes in T cell development. In mature T cells, inactivation of TGF?R3 enhanced Th1 differentiation but diminished Th17 differentiation. These results reveal an indispensable function for TGF?R3 in T cell development and differentiation. TGF?R3 is a coreceptor and enhances the binding of TGF-? family of molecules to TGF?R1/TGF?R2 heterodimer leading initiation of intracellular signals. TGF?R3 also binds to inhibins with high affinity to antognize activin-dependent signaling. In addition to TGF?R1/TGF?R2 associated activity, TGF?R3 can also independently modulate intracellular signals associated with activation and migration. For this proposal, the specific aims are: (1) to determine the role of TGF?R3 in T cell development and selection; (2) to determine the role of TGF?R3 in modulating the differentiation of na?ve T cells to effector cells and autoimmunity. Our proposed studies will move the field forward in our understanding of the biological properties of TGF-? family of proteins with opportunities to develop new strategies for promoting immunity and/or targeting autoimmunity.

Public Health Relevance

The goal of this proposal is to study the function of a poorly understood cell surface expressing protein called transforming growth factor receptor 3 (TGF?R3) in immunity and autoimmunity. The lack of this protein leads to embryonic lethality; therefore we developed a novel mouse model in which TGF?R3 can be conditionally deleted in selected tissues to dissect its role in the immune response. The approach in this proposal will set a path for the development of new strategies for modulating the immune response and/or treat autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI107748-02
Application #
8891356
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Singleton, Kentner L
Project Start
2014-08-01
Project End
2017-07-31
Budget Start
2015-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294