Study reveals how fine-tuning the immune system can improve vaccines, reduce disease severity

Immunologists at St. Jude Children’s Research Hospital have discovered a molecular route that regulates how crucial immune cells known as T follicular helper cells evolve into the immune system’s functioning components.

Hongbo Chi, PhD, of the St. Jude Department of Immunology, identified a biological pathway that selectively controls how key immune cells mature into functional components of the immune system. Image Credit: St. Jude Children’s Research Hospital.

The discovery suggests that medications to activate the metabolic pathway could be developed to improve the efficacy of vaccines, particularly those that protect against COVID-19. Such drugs may encourage the immune system to respond more quickly after immunization, resulting in the production of more antibodies against a virus or bacterium.

The research also sets the groundwork for medications that slow down the pathway, which could help people with autoimmune illnesses like lupus. A hyperactive immune system produces antibodies that assault the body’s own tissues in such illnesses.

The researchers, led by Hongbo Chi, Ph.D., of the Department of Immunology, recently published their results in Nature.

Regulating the adaptive immune response

Chi and his team investigated a metabolic control route in the adaptive immune system that regulates the formation of specialized immune cells selectively. T follicular helper cells are the name for these cells.

When the body is attacked by viruses or bacteria, the adaptive immune system learns to target and attack those viruses or bacteria. T follicular helper cells activate humoral immunity, a component of the adaptive immune system.

Humoral immunity targets intruders circulating outside cells primarily through the production of antibodies, whereas cellular immunity targets invaders within diseased cells.

The researchers wanted to see in their trials whether there was a metabolic regulatory pathway that transformed T follicular helper cells to activate them. When these cells are activated, they promote the maturation and production of infection-fighting antibodies by B cells, which produce antibodies.

Discovering a key pathway

To find a viable regulatory pathway, Chi and his team employed genetic approaches to knock off numerous enzymes that are known to be involved in metabolic regulation pathways in T cells. The scientists next inoculated the deletion-engineered T cells into mice and evaluated whether the T cells without the enzyme were functional after infection with a virus.

Their research indicated that the CDP-ethanolamine pathway, a metabolic regulatory mechanism, preferentially regulates T follicular helper cells.

This finding was a big surprise. First of all, this pathway was considered to have a housekeeping function leading to the production of building blocks for the cell membrane. But we discovered that it has a major signaling function. And secondly, we were surprised that this pathway—and not other parallel pathways of this type—was the only one involved in regulating T follicular helper cells.”

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

The researchers used a supplementary strategy to see whether the CDP-ethanolamine route specifically regulated T follicular helper cells: they eliminated each of the main enzymes they found in the process.

They discovered that knocking down these enzymes, but not those in other parallel regulatory pathways, affected T follicular helper cell growth but not overall immune function.

Importantly, those important enzymes, according to Chi, could be targets for medications that either promote or inhibit the system and therefore T cell activation.

We are now exploring whether we can enhance the effectiveness of vaccines by using drugs that activate the pathway, to help these T cells mobilize the immune system to generate antibodies in response to a vaccine.”

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

“On the other hand, to treat autoimmune disease, we’re interested in developing new ways to inhibit this pathway. This approach is promising because we know that such activation or inhibition is highly selective for T follicular helper cells and would not affect other immune functions,” added Chi.

The researchers are also looking at the structural mechanisms that the enzymes use to function, which could lead to therapeutic targets, according to Chi.