After repeated exposure to a fragment of the myelin protein — the target of autoimmune attack in multiple sclerosis (MS) — immune cells in mice were reprogrammed to be tolerant to myelin, suppressing the immune response associated with the disease, a study revealed.
Researchers showed that in these tolerant T-cells, genes that limit immune responses were enhanced, while genes that activated T-cells were repressed.
These findings support the development of therapies that directly address the underlying autoimmune response in MS patients.
The study, “Chromatin Priming Renders T Cell Tolerance-Associated Genes Sensitive to Activation below the Signaling Threshold for Immune Response Genes,” was published in the journal Cell Reports.
MS is characterized by the immune system mistakenly attacking myelin — the fatty protective coating that covers nerve fibers. T-cells are a type of immune cell that is involved in the autoimmune attack against the myelin sheath and represents a target for MS treatments.
The process of T-cell activation against an antigen — molecules capable of stimulating an immune response — is tightly regulated and depends on multiple signaling pathways to ensure an appropriate immune response.
A recent review analysis demonstrated that T-cell activation could be suppressed by repeated exposure to an antigen, leading to so-called T-cell tolerance against that antigen. This represents a type of immunotherapy with the potential to desensitize the immune system.
Understanding the mechanism of this phenomenon may help researchers find ways to reprogram T-cells to become tolerant and not attack the myelin sheath, which may lead to effective therapies to treat the underlying cause of MS.
A team led by researchers at the University of Birmingham, U.K., conducted a genetic analysis on T-cells before and after becoming tolerant.
Researchers used a special breed of mice (Tg4) in which T-cell tolerance was induced by exposing the animals to increasing doses of a piece of the myelin basic protein (MBP), a component of the myelin sheath and autoimmune target in MS. Normal mice with “non-tolerant” T-cells served as a control group.
The genetic analysis of mouse T-cells showed that when repeatedly exposed to MBP, signals to genes involved in T-cell suppression were enhanced, whereas signals to genes involved in T-cell activation were blocked, together silencing the immune response.
To understand how these genes were turned on and off, the team looked more in-depth at epigenetic mechanisms — the process of gene activation (turn on) and suppression (turn off).
In chromosomes, DNA is wrapped around proteins called histones to form a structure known as chromatin. For a gene to be activated and read, the DNA must be unraveled from the histones in a process called chromatin priming.
To test which genes are activated, an enzyme was used that cuts DNA (DNase I) when unraveled and exposed, whereas inactive genes will be protected from the enzyme’s action.
The genes from tolerant T-cells leading to immune suppression were susceptible to the enzyme, thus turned on. In contrast, genes that activated T-cells were protected, therefore turned off.
In comparison, this process of chromatin priming played a small role in healthy T-cell responses, suggesting that tolerant T-cells were reprogrammed by repeated MBP exposure and retained the memory of this change.
Overall, the results show “how repeated exposure to antigens causes an altered epigenetic state leading to T-cell … tolerance, representing a basis for treating auto-immune diseases,” the researchers wrote.
“This study has led us to finally understand the underlying basis of immunotherapies which desensitize the immune system,” Peter Cockerill, PhD, a study co-author and professor at the Institute of Cancer and Genomic Sciences at the University of Birmingham, said in a press release.
“These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat,” said David Wraith, PhD, study co-author and professor at the Institute of Immunology and Immunotherapy.
According to the research team, more studies are needed to determine whether antigen-specific immunotherapies can have lasting benefits.
