Early nutrient availability is a key driver of T-cell exhaustion

Some immunotherapies, especially those used to treat cancer, utilize the critical role T cells play to target and destroy diseased cells. However, T-cell exhaustion presents a significant obstacle to this approach, wherein T cells are overworked and cease to function effectively. Research at St. Jude, led by corresponding author Doug Green, PhD, Department of Immunology, has shed new light on the mechanisms behind T-cell exhaustion. The study revealed that exhaustion can be initiated during the earliest stages of T-cell activation and is influenced by the available levels of the amino acid, methionine. Cancer cells deplete methionine in the tumor microenvironment, impairing T-cell function. The researchers found that methionine supplementation prevented T-cell exhaustion and increased antitumor immunity. 

“We are the first group to demonstrate mechanistically that during the early activation phase, nutrient availability can drive cells toward exhaustion,” explained first author Piyush Sharma, PhD, Department of Immunology. “It’s not just persistent antigen exposure; other factors, present very early in the activation process, can also push cells toward exhaustion.” 

“This research has revealed something remarkable: Even simple nutrients can have profound effects on the immune system,” said Green. “Our future research will focus on identifying other nutrients that, when increased or decreased, could enhance the body’s anticancer or antiviral responses.”

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