The body needs regulatory T cells (Tregs) on the sidelines of an immune attack, making sure tempers don’t run too hot and preventing the body’s lymphocytes from taking the body’s own cells. Because of this vital role, scientist strive to pinpoint the key mechanisms for Treg function and survival. The newest research calls on Sharpin, formally known as SHANK-Associated RH Domain Interactor, a protein involved linear polyubiquitination and associated with “inappropriate inflammation” (Gene Cards
From the La Jolla Institute for Allergy and Immunology, Yun-Cai Liu, PhD, and his team set out to decipher definitively the relationship between Sharpin and Tregs. Their study was published in Nature Immunology
earlier this month.
"Treg-based intervention has in fact been proposed as a novel therapeutic means to treat various inflammatory diseases, meaning that knowing how Treg function is regulated could speed development of effective treatments,” said study co-author Hyung-seung Jin.
To study the functionality of Tregs, the researchers observed mice that lacked any Sharpin protein. Not long after being born, the Sharpin knock-out mice developed skin lesions and internal inflammation, despite being free of any infections. The last clue was the low Treg cell count in all tissues, even in the thymus where all T lymphocytes develop. These outcomes strongly linked a lack of Sharpin to low numbers of Tregs, which resulted as expected in unnecessary inflammatory responses.
The team also replenished the Treg population in the knock-out mice by injecting healthy Tregs from normal mice who were born with Sharpin. They saw a clear reduction in inflammation severity.
Without the “cell survival mechanism” provided by Sharpin during Treg development, the lymphocytes die in the thymus. A single mutation in the genes coding for Sharpin could lead to autoimmune disease. Now scientists will know to check for Sharpin proteins in cases of autoimmune disease where Treg levels are low all over the body. If a lack of Sharpin ends up being the cause of disease, a treatment of healthy Tregs with ample Sharpin to keep them alive, similar to the replenishment done in this study, could potentially help people with autoimmune disease.
Also promising are the applications for cancer treatments made possible with this discovery. Scientists could carefully take advantage of Treg dependence on Sharpin for survival when fighting tumors in certain tissues. By limiting Sharpin production in certain tissues, killer lymphocytes like cytotoxic T cells could experience enhanced tumor recognition and attack more efficiently, behaviors which are usually heavily monitored and inhibited by Tregs.
Source: La Jolla Institute for Allergy and Immunology