FOCIS 2015: Metabolism May Affect Immune System’s Reaction to Disease

The fighting force of immunological memory is made up of both B cells and T cells, the latter of which can recognize a pathogen after its first encounter and kill it before it has a chance to wreak havoc on the immune system.

“We’ve been very interested in how protective immunity is formed,” said Dr. Goldrath.

The smallpox vaccine is an important example of immune memory, she said. A majority of people who were given the vaccine retain memory T cells that keep them protected against the highly contagious virus “for their entire lifetime for many individuals,” she noted.

Dr. Goldrath

Dr. Goldrath and her team set out to explore what allows T cells to transition from effector cells to memory cells that can recognize dangerous repeat invaders. In particular, they wanted to figure out “what has to go right” in the process to ensure activation of the preferred immunity response and the signals involved, she said.

“First and foremost, it’s worth noting that immunological memory is mediated by diverse heterogeneous cell populations,” said Dr. Goldrath. “While a lot of people spent a lot of time trying to tease apart what the signals are that will give immunological memory, it appears that this heterogeneous population is relying on a range of signals.”

It’s possible to conduct experiments and predict whether cells will differentiate to short-lived terminal effectors, which clear initial infection and sustain protection for months to come, or instead generate longlived memory CD8+ T cells that have a renewal capacity and can combat second infection. However, cells are in fact integrating all of the signals early on in the activation process, noted Dr. Goldrath.

Because it is known that T cells in the tissue are exposed to hypoxic signals, Dr. Goldrath and her fellow researchers began to explore inhibitory receptors that are regulated by hypoxia inducible factor (HIF), protein that drives gene expression in response to a reduction of oxygen. At the cellular level, HIF’s immune function is to react whenever oxygen drops to critical levels, signaling genes to respond in various ways to combat the effects of hypoxia.

Researchers looked at connections between hypoxia and transcriptional signals that lead to T cell differentiation. There are a variety of signals that are downstream of HIF, with glycolysis often being the most eminent, Dr. Goldrath said.

Sustained HIF helps power glycolytic activity along the metabolic pathway through a series of changes and transformations. Hypoxia-inducible Factors 1 and 2 also contribute to the glycolytic switch observed during T cell expansion, according to Dr. Goldrath.