Regulatory T (Treg) cells play a dominant role in controlling immune responses by the suppression of other effector T cells to prevent excessive reactions to benefit the body. On the other hand, Tregs are recruited to and induced by tumor cells, which results in hampering protective anti-tumor immunity to cause body damage. However, the detailed mechanisms for Treg-mediated immune tolerance are poorly characterized. The E3 ligase component Fbw7 mediates the turnover of multiple proto-oncogenes that are broadly implicated in tumorigenesis such as the T cell acute lymphoma. However, whether Fbw7 signaling is crucial to Treg cell function remains unknown. We initiated this project by generating Foxp3+ Treg cell-specific deletion of Fbw7 in mice. Notably, Fbw7f/f Foxp3-YFPcre mice showed markedly reduced lung metastasis and we also found that an enhanced activation and cytokine production by conventional T cells. In addition, Fbw7 belongs to a family of WD-domain containing E3 ligases with ~26 members, and most of them have not been characterized so far. We hypothesize that the E3 ligase component Fbw7 and its family members play overlapping or redundant roles in immune tolerance by regulating the function of Treg cells. To test this hypothesis, we propose the following two Specific Aims:
Specific Aim 1. To study the cellular and molecular mechanisms of Fbw7 in Treg cells, and Specific Aim 2. To study Fbw family members in Treg cells. This exploratory R21 application will allow us to study a novel function of the E3 ligase component Fbw7 and its family members in immune tolerance and anti-tumor immunity. The expected results will significantly advance our knowledge on the basic biology of the ubiquitin system in immune regulation, and on the translational aspect of harnessing Treg cells in immunotherapy.

Public Health Relevance

Regulatory T cells play a dominant role in controlling immune responses by suppressing the activation and function of other lymphocytes, and are involved in the inhibition of anti-tumor immunity. This proposal will study the molecular and cellular mechanisms by which the immune responses are properly controlled by this special population of T cells. Such knowledge will eventually facilitate the design of novel therapeutic approaches for human immunological diseases and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI126487-01A1
Application #
9462515
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Ramachandra, Lakshmi
Project Start
2017-12-07
Project End
2019-11-30
Budget Start
2017-12-07
Budget End
2018-11-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037