Study reveals metabolic signaling pathways that influence key immune cells

Effector regulatory T cells, also known as eTreg cells, are a specialized subset of white blood cells that maintain the immune system.

Study reveals metabolic signaling pathways that influence key immune cells
From left to right: Author Nicole Chapman, PhD, Immunology; first author Wei Su, graduate student; and corresponding author Hongbo Chi, PhD, Immunology, studied how to better understand and treat inflammatory diseases through regulating T cells. Image Credit: St. Jude Children’s Research Hospital.

Now researchers from St. Jude Children’s Research Hospital have demonstrated the metabolic signaling mechanisms that control the function of eTreg cells. The study may support efforts to gain a better understanding of inflammatory diseases and treat them accordingly.

The results of the study were recently published online in the Cell Metabolism journal.

This process is quite fascinating to us, and helps explain how metabolites can drive selective signaling pathways to enforce the differentiation, persistence and function of eTreg cells. We were looking specifically at suppression of autoimmunity that can develop spontaneously in our models, but we also know Treg cells play a role in multiple diseases.”

Hongbo Chi, PhD, Study Corresponding Author, Department of Immunology, St. Jude Children’s Research Hospital

While eTreg cells play a role in the prevention of autoimmune diseases, such as rheumatoid arthritis and lupus, they are detrimental in other disorders, for example, cancer.

Interpreting how metabolic signaling controls the function and heterogeneity of eTreg cells may allow researchers to develop more specific medications to target these routes to help treat various diseases. How these metabolic pathways control the persistence and differentiation of eTreg cells, specifically at the level of intracellular signaling, was not clear, until now.

Metabolic pathways exert control

The team demonstrated that two-way metabolic signaling that crisscrosses with T cell receptor signaling is crucial to control the function of eTreg cells.

Scientists discovered a group of metabolites known as isoprenoids. These metabolites are crucial for the suppressive activity of activated Treg cells, like eTreg cells. They are also needed for cellular processes known as posttranslational lipid modifications, particularly protein farnesylation and geranylgeranylation.

Such cellular processes are controlled by Fntb and Pggt1b, in that order. When these processes are disrupted by Treg cell-specific deletion of Pggt1b or Fntb, it causes mice to develop autoimmunity.

Additional studies into the metabolic signaling mechanisms disclosed the distinct details of Treg cell-mediated immune suppression downstream of T cell receptor signaling. Furthermore, Fntb works through two parallel routes—the immune receptor called ICOS, and the protein kinase mTORC1, which controls the metabolic reprogramming of Treg cells—to support the persistence of eTreg cells. Pggt1b enforces signaling via the small G protein Rac to promote the differentiation of eTreg cells.

According to Wei Su, the study’s first author and graduate student of St. Jude Immunology, “We were able to dissect how metabolic regulation controls eTreg cell differentiation and maintenance. This bidirectional interplay between intracellular signaling and metabolism allows eTreg cells to maintain the self-tolerance in our body.”

These pathways have been of long-standing interest outside of the immune system for a way to inhibit inflammatory responses. Our study provides a deeper understanding of the molecular interplay between signaling and metabolism and could allow for more potent and selective targeting of downstream metabolic functions in Treg cells.”

Nicole Chapman, PhD, Study Author, Department of Immunology, St. Jude Children’s Research Hospital

Source:
Journal reference:

Su, W., et al. (2020) Protein Prenylation Drives Discrete Signaling Programs for the Differentiation and Maintenance of Effector Treg Cells. Cell Metabolism. doi.org/10.1016/j.cmet.2020.10.022.

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