New Understanding of eTreg Cells Signals Hope for Inflammatory Diseases
Scientists at St. Jude Children’s Research Hospital have revealed insight into the metabolic signaling pathways influencing eTreg cells that could lead to new therapies for inflammatory diseases and related disorders.
Effector regulatory T cells, also known as eTreg cells, are a specialized subset of white blood cells responsible for maintaining the immune system. While effector T cells promote inflammation, regulatory T (Treg) cells control it, so they play a critical role in the prevention of autoimmune diseases like rheumatoid arthritis and lupus, which share a similar immune system malfunction.
The role of eTreg cells in the body is a fine balance, however, as they have a detrimental impact in diseases like cancer. Gaining a deeper understanding of how metabolic signaling controls their function and heterogeneity could open the door for researchers to develop more specific medications to target these routes.
How metabolic pathways control the persistence and differentiation of eTreg cells, specifically on the intracellular signaling level, was previously unclear. Dr. Nicole Chapman, Ph.D., a staff scientist in St. Jude’s Department of Immunology, explained the significance of her team’s findings.
“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 eTreg cells,” said Chapman.
Other key findings from the study, originally published in the Cell Metabolism journal and co-authored by graduate student Wei Su, and Dr. Hongbo Chi, Ph.D., also of St. Jude, shed light on how these eTreg cells are impacted by metabolic signaling pathways.
Specifically, they showed that two-way metabolic signaling that crisscrosses with T cell receptor signaling is critical for Treg cell function. They also uncovered a group of metabolites called isoprenoids which are crucial for the suppressive activity of eTreg cells and are also required for cellular processes called posttranslational lipid modifications, especially protein farnesylation and geranylgeranylation.
The study found that when these processes are disrupted by eTreg cell-specific deletion of PggtIb or Fntb, mice developed autoimmunity, providing a potential key to future therapies for the disorder.
“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,” stated corresponding author Chi.
Added first author, Su:
“We were able to dissect how metabolic regulation controls eTreg cell differentiation and maintenance. This bidirectional interplay between intracellular signaling and metabolism allows cells to maintain the self-tolerance in our body.”