Scientists at La Jolla Institute for Immunology investigate powerful protein behind antibody development

Shane Crotty of the La Jolla Institute for Immunology led new research on a protein called Bcl6.
New research led by Shane Crotty of the La Jolla Institute for Immunology gives scientists a guide to how they could potentially switch a protein called Bcl6 on or off to control immune responses, Crotty said.

Scientists at the La Jolla Institute for Immunology have discovered a potential new way to better fight a range of infectious diseases, cancers and autoimmune diseases.

A new study published by Nature Immunology shows how a protein works as a “master regulator” in the immune system. The research is an important step toward designing vaccines and therapies that can “switch on” the immune cells that help produce disease-fighting antibodies. Scientists also may be able to “switch off” those cells to counteract immune cell dysfunction in autoimmune diseases.

“This cell type (Tfh cells) sometimes does bad things in autoimmune diseases — particularly autoantibody diseases like lupus, rheumatoid arthritis and Sjogren’s syndrome,” said LJI investigator Shane Crotty, who led the new research. “So hopefully, our fundamental knowledge about the circuitry of this cell can help us understand how to turn it off in autoimmune diseases.”

Crotty’s laboratory studies key immune system players such as different kinds of helper T cells. In 2009, his laboratory published work showing that a protein called Bcl6 controls how helper T cells differentiate to do different jobs in the body. Researchers found that Bcl6 prompts helper T cells to become Tfh (T follicular helper) cells, which work with B cells to produce powerful antibodies.

But Crotty’s lab still wanted to know exactly what Bcl6 was doing to Tfh cells. Answering that question could open the door to controlling immune responses.

“There is great interest in the use of Tfh-cell-associated biology for enhancement of vaccines,” Crotty said. “There is also great interest in targeting Tfh-cell-associated biology for therapeutic interventions in human autoimmune diseases, allergies, atherosclerosis, organ transplants and cancer.”

For the new study, researchers used mouse models and a range of genetic sequencing tools to determine that Tfh cells need Bcl6 to even exist.

Bcl6 blocks the expression of two proteins that normally stop Tfh cell differentiation. When Bcl6 does its job, helper T cells are free to become Tfh cells when the body needs them.

The new research gives scientists a guide to how they could potentially switch Bcl6 on or off to control immune responses, Crotty said. “Increasing emphasis will surely now be placed on how to apply that knowledge to Tfh-related therapeutics,” he added.

The body also uses the kinds of genetic circuits controlled by Bcl6 to stay healthy and not produce antibodies that mistakenly attack the body’s own cells.

“The system needs to self-correct and stop the attack. If an immune response is needed to fight off a pathogen, the body needs to reset itself and return to a steady state,” Crotty said.

But deficiencies in the Bcl6-Tfh system can lead to autoimmunity or immunodeficiency. The new research suggests that tweaking immune responses through Bcl6 could help control autoimmune diseases such as multiple sclerosis and Type 1 diabetes.

Via Bcl6, Tfh also can theoretically be tuned down to treat allergies and help prevent atherosclerosis, the buildup of fats, cholesterol and other substances in and on the artery walls that can restrict blood flow.

Better cancer treatments also could include tweaking Tfh to decrease unwanted immune responses to therapy, Crotty said.

The study was supported by grants from the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases, and internal La Jolla Institute funds.

La Jolla Light staff contributed to this report.