Our long-term goal is to study the protein ubiquitination pathway in immune regulation. We initiated a new study of the deubiquitinating enzyme CYLD in Tregs by using CYLD floxed Foxp3-cre mice, We found that deficiency of CYLD in Tregs caused chronic lung inflammation. A preliminary study showed that those mutant Tregs expressed altered patterns of chemokine receptors and increased IL-4 production. These preliminary studies pointed to new mechanisms of CYLD regulation of Tregs, via modulating their homing/migration and cytokine production, and they highlight potential tissue-specific aspects of Treg function. These preliminary studies thus provide us with a solid basis for testing our central hypothesis that the ubiquitination/deubiquitination system plays a critical role in the regulation of immune via modulating the homing and/or function of Tregs to particular tissues. Here we plan to test this hypothesis by proposing three Specific Aims:
Aim 1, to study CYLD in Treg regulation in the lung;
and Aim 2, to study the mechanistic regulation of CYLD-/- Tregs. The expected results will significantly advance our basic knowledge on the context-dependent regulation of Tregs by the protein deubiquitination pathway, and will provide clues to therapeutic intervention of human diseases by harnessing Tregs.
This R21 application will study the essential role of a protein enzyme responsible for the removal of conjugated ubiquitin from a protein substrate in immune regulation. The immune system is capable to mount robust responses against invading pathogens, but at the same time is tolerant to self-tissues or self-antigens. The mechanisms governing self-protection or immune tolerance are far from clear. The study of such mechanisms is very critical, since breakdown of immune tolerance results in disastrous consequences like the development of autoimmune diseases. This proposal will study the molecular and cellular mechanisms by which the immune responses are properly controlled by a special population of T cells. Such knowledge will eventually facilitate the design of novel therapeutic approaches for human immunological diseases.
| Park, Yoon; Jin, Hyung-Seung; Lopez, Justine et al. (2016) SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nat Immunol 17:286-96 |
