Remember me: immune cell discovery could improve vaccines

The immune system has a long memory. Once exposed to certain pathogens, specialised immune cells spring into action and produce antibodies against the pathogen, allowing the rest of the immune system to hunt it down and eliminate it.

However, the process behind immune memory has long been murky. Now researchers from the Walter and Eliza Hall Institute (WEHI) have uncovered a key piece of the puzzle: the characterisation and fate of T follicular helper cells (T_FH cells).

T_FH cells play a critical role in antibody production and developing long-lasting immunity.

However, the cells are also dramatically increased in chronic inflammatory disease, suggesting that they could be a therapeutic target for treating these diseases.

Immune memory is also a crucial aspect of vaccination programmes, which are intended to trigger such immunity against killed or attenuated pathogens, or their component parts.

Thus understanding how T_FH cells develop may help improve future vaccines, particularly those that don’t presently offer long term immunity, such as cholera, which requires regular boosters.

The research team was led by Dr Katja Lüthje and Associate Professor David Tarlinton, from WEHI’s Immunology division, and Dr Stephen Nutt from the institute’s Molecular Immunology division

They discovered a means of identifying T_FH cells while they are actually involved in instructing the immune response, revealing for the first time the possible fates of these cells.

To track the development and fate of the cells, they used a mouse model that expressed green fluorescent protein wherever the protein interleukin 21 (IL-21) was also expressed. As IL-21 is associated with T_FH cells they were able to track the development of the cells within the mice.

Dr Nutt said that one of the key findings made by the researchers was that T_FH cells can remember being exposed to infectious agents, allowing them to rapidly react to subsequent attacks.

“The success of vaccines relies on antibody production and long-term immune ‘memory’; without these, most routinely-used vaccines, including measles, mumps and tetanus, do not work,” he said.

“It is well established that antibody-producing B cells can remember a particular infectious agent and rapidly respond if and when they come across it again. Our study shows, for the first time, that T follicular helper cells also develop memory to rapidly respond to infection.

“This finding is incredibly important for the development of vaccines, which relies on immune memory to prevent subsequent infections,” Dr Nutt said.

“Some vaccines, such as polio are very effective at establishing long-term immunity, while others, such as the cholera vaccine are not particularly effective and need ongoing boosters. It may be that the vaccines are not establishing good T follicular helper cell memory, and this could be something to look at for developing new vaccines for diseases that currently do not have good preventive treatments.”

The researchers were also surprised to find that T_FH cells gave rise to memory T cells with high plasticity, which allowed them to differentiate into different types of immune cell.

“We found that T follicular helper cells are pretty flexible, adapting to carry out several different functions depending on where they are needed,” said Associate Professor Tarlinton.

He said the research team also discovered that T follicular helper cell numbers are tightly controlled by the immune system, which might explain why increases in their numbers are associated with chronic inflammatory diseases, which include rheumatoid arthritis, Type 1 diabetes, lupus and multiple sclerosis.

“In some models, a large increase in the numbers of T follicular helper cells is associated with the development of chronic inflammatory, or what we call autoimmune, diseases in which the immune system attacks its own tissues,” he said.

“In fact, it has been found that T follicular helper cells, in mouse models, were actually the cause of an autoimmune disease very much like lupus in humans. This suggests that modulating these cells could be a potential treatment for autoimmune conditions.”

The study was published in Nature Immunity this morning.