Metabolic signaling points to new targets in autoimmune diseases

Understanding how metabolic signaling affects regulatory T-cell diversity may aid the development of drugs to specifically target these pathways, St. Jude researchers said. (St. Jude Children's Research Hospital)

A group of specialized white blood cells called regulatory T cells, or Tregs, is crucial to keeping the immune system in check. The cells' immunosuppressive functions can be affected by metabolic signaling that leads to autoimmune diseases, but the exact cellular mechanisms behind this phenomenon are largely unknown.

Scientists at St. Jude Children’s Research Hospital have now shed some light on how two-way metabolic signaling intersects with T-cell receptor (TCR) intracellular signaling, providing critical support to Tregs. They published the findings in Cell Metabolism.

The researchers believe their discovery could help identify new ways to treat inflammatory diseases such as lupus and rheumatoid arthritis as well as other illnesses in which Treg cells are implicated, including cancer. Further understanding how metabolic signaling regulates Treg cell diversity may aid the development of drugs to specifically target these pathways, they believe.

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The ability of Tregs to suppress diverse inflammatory responses requires that they differentiate into effector Treg cells, or eTregs. So that's where the St. Jude team focused their research efforts.

The researchers identified a group of metabolites called isoprenoids that are critical for Treg cells to become eTregs and take on their suppressive powers. These compounds require certain cellular processes, specifically two that are mediated by the enzymes Fntb and Pggt1b, the team showed. Deleting the two enzymes in Treg cells—but not conventional T cells—led to autoimmune disease in mice, confirming their roles in Treg cell-mediated immune balance.

Further analysis showed that mice that lacked the two enzymes had pronounced reductions in eTreg cells, indicating Fntb and Pggt1b affected eTreg cell accumulation.

Turns out, Fntb and Pggt1b affect TCR signaling in different ways. Fntb maintains some eTreg cells via mTORC1 and ICOS, the team found. mROC1 is known to regulate certain metabolic processes that reprogram Treg cells to govern their functions.

As for Pggt1b, the team described it as a "rheostat" for TCR signaling. That means it’s key in promoting Treg cell adhesion to antigen-presenting dendritic cells—a critical step for the cells to be able to receive TCR signals. It also enforces other protein signals that support eTreg cell differentiation, the researchers found.

RELATED: Fine-tuning regulatory T cells to treat cancer and autoimmune diseases

Because Tregs play a critical role in striking the balance between immune response and immune self-tolerance, they are a popular target among researchers studying inflammatory diseases, and they have attracted interest from Big Pharma companies.

Novartis’ venture arm recently backed the seed funding of a Boston startup called GentiBio, which focuses on developing Treg cell therapies to restore immune tolerance.

Roche recently penned a near-$800 million deal with Rheos Medicines to work on new drugs in immunometabolism that “modify the fate or function of certain human immune cells.”

The St. Jude’s research “helps explain how metabolites can drive selective signaling pathways to enforce the differentiation, persistence and function of eTreg cells,” Hongbo Chi, Ph.D., the study’s corresponding author, said in a statement. That insight “may provide opportunities to selectively modulate Treg cell activity in autoimmune, cancer and infectious diseases,” the researchers wrote in the study.

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