Source: The Third Affiliated Hospital
Written by: The Third Affiliated Hospital
Edited by: Wang Dongmei

A Joint group from Song Guo Zheng Lab in Center for Clinical Immunology of The Third Affiliated Hospital at Sun Yat-sen University and Bin Li Lab at Institute Pasteur of Shanghai identify a key molecular pathway for the inactivation of Treg cells after sensing inflammation. This novel finding was just published on Proceedings of the National Academy of Sciences of the United States of America (PNAS) on June 10, 2015.

Regulatory T cells (Treg) play a crucial role in controlling immune balance. Activity of the forkhead family transcription factor FOXP3 determines the immune function of FOXP3+Treg cells. Upon infection or other inflammatory conditions, FOXP3+Treg cells usually suppress effector immune cell responses leading to the failure of clearing infection or autoimmunity. Tregs may also help to limit collateral tissue damage during heightened inflammation. It still remains unknown how Treg cells sense inflammation and shut down its immune suppressive activity to allow immune activation to occur. Dr. Zheng group and other scientists have previously found that Treg cells are unstable in the inflammation condition, thus, understanding on the regulation of FOXP3 stability and its dynamic ensemble of enzymatic cofactors in Tregs could provide therapeutic clues on how to control major inflammatory diseases including autoimmunity and allergic diseases.

Researchers from this joint group observed that a new molecule, Deleted in breast cancer 1 (DBC1), binds to FOXP3 and promotes FOXP3 degradation at the protein level in response to inflammatory insult. Using tandem affinity purification, researchers found that DBC1 is a previously unidentified subunit of FOXP3 complex. Data clearly revealed that the linker region between the leucine zipper motif and the forkhead domain of FOXP3 interacts with the N-terminal 200 amino acid region of DBC1. Knockdown of DBC1 in FOXP3+Treg cells prevented caspase 8-mediated degradation of FOXP3 under inflammatory cytokine stimulation. Moreover, scientists demonstrated that more Treg cells existed in Dbc1-/- mice, and Dbc1-/- FOXP3+Treg cells are more functionally potent compared to Treg cells in wild type mice. Thus, they propose that DBC1 may act as a negative regulator of FOXP3 by attenuating FOXP3 protein stability and activity under inflammation, which could represent a novel molecular pathway for therapeutically modulating FOXP3+ Treg function.

Dr. Zheng has long been engaged in the induction, development, maintenance and their respective mechanisms of Treg cells for many years. He and his co-workers invented the TGF-β-induced regulatory T cells in the world. He has made a very important contribution to the phenotype, functional characteristics, development, and differentiation of FOXP3+ Treg cells in the field. His achievement is remarkable on the manipulation of Treg cells and their use in the prevention and treatment of autoimmune diseases and organ transplantation rejection.

The study entitled “Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1” (www.pnas.org/content/early/2015/06/08/1421463112) has been published online in PNAS.

This work was in part supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China and the leading talent investigator award from Sun Yat-sen University.