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Metabolic signaling plays a crucial role in regulating specialized T cells

Scientists at St. Jude Children’s Research Hospital have identified how metabolic signaling pathways influence key immune cells with implications for treating autoimmune disorders and cancer.

Memphis, Tennessee, November 17, 2020

Three researchers in masks and labcoats stand in front of a building.

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.

Effector regulatory T cells (eTreg cells) are a specialized subset of white blood cells that keep the immune system in check. St. Jude Children’s Research Hospital scientists have revealed the metabolic signaling mechanisms that regulate function of eTreg cells. The work may aid efforts to better understand and treat inflammatory diseases. The findings were published online today in Cell Metabolism.  

“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,” said corresponding author Hongbo Chi, Ph.D., of St. Jude Immunology. “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.”

Although eTreg cells are involved in prevention of autoimmune diseases, including lupus and rheumatoid arthritis, they are detrimental in other diseases, such as cancer. Understanding how metabolic signaling regulates Treg cell heterogeneity or function may help scientists develop more specific drugs to target these pathways to help treat disease. How metabolic pathways regulate the differentiation and persistence of eTreg cells, especially at the level of intracellular signaling, has been unclear until now.

Metabolic pathways exert control

The researchers showed that two-way metabolic signaling that intersects with T cell receptor signaling is critical to regulating eTreg cell function.

Investigators identified a class of metabolites called isoprenoids that are essential for the suppressive activity of activated Treg cells such as eTreg cells. Isoprenoids are required for cellular processes called posttranslational lipid modifications, specifically protein farnesylation and geranylgeranylation. These processes are mediated by Fntb and Pggt1b, respectively. Disruption of these processes by Treg cell-specific deletion of Fntb or Pggt1b causes mice to develop autoimmunity.

Further research into the metabolic signaling mechanisms revealed the discrete details of Treg cell-mediated immune suppression downstream of T cell receptor signaling. Fntb acts through two parallel pathways to promote eTreg cell persistence: the protein kinase mTORC1, which regulates metabolic reprogramming of Treg cells, and the immune receptor ICOS. Pggt1b enforces signaling through the small G protein Rac to support eTreg cell differentiation.

“We were able to dissect how metabolic regulation controls eTreg cell differentiation and maintenance,” said first author and graduate student Wei Su of St. Jude Immunology. “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,” said study author Nicole Chapman, Ph.D., of St. Jude Immunology. “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.”

The other authors were Jun Wei, Hu Zeng, Yogesh Dhungana, Hao Shi, Jordy Saravia, Peipei Zhou, Lingyun Long, Sherri Rankin, Anil KC and Peter Vogel, all of St. Jude; and Hu Zeng, formerly of St. Jude and now of Mayo Clinic. 

The research was funded in part by grants from the National Institutes of Health (AI1055887, AI131703, AI140761, Q9 AI150241, AI150514, CA221290) and ALSAC, the fundraising and awareness organization of St. Jude.

 
 

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20 percent to 80 percent since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food — because all a family should worry about is helping their child live. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.