Scientists from Monash University’s Biomedicine Discovery Institute report that they have made a critical advance in the understanding of a new facet of the immune response to malaria, which could help in the development of a vaccine.

Malaria is caused by an infection with a deadly parasite species called Plasmodium falciparum and although it is one of the world’s most prevalent global diseases, efforts to develop an effective vaccine have been restricted by a lack of understanding of the immune response that drives immunity. The World Health Organization estimates there are 200 million infections and 500,000 deaths each year as a direct result of malaria.

The new study (“Repeated Plasmodium falciparum infection in humans drives the clonal expansion of an adaptive γδ T cell repertoire”) in Science Translational Medicine found that a poorly understood group of immune cells, called gamma delta T cells, were directly involved in promoting clinical protection from malaria. These gamma delta T cells express a unique T-cell receptor (TCR) that was involved in the recognition of P. falciparum parasite fragments.

By using human samples from clinical trials exploring the natural immune response to malaria, the scientists were able to obtain a detailed map of how gamma delta T cells and the gamma delta TCR respond to repeated seasonal and experimental P. falciparum infections.

While many aspects of the immune system’s defense mechanisms are actively avoided or dampened by the complex life cycle of P. falciparum, gamma delta T cells were highly responsive and evolved to tolerate repeated P. falciparum infections. This work reshapes the understanding of how these T cells interact with dangerous pathogens and provides new avenues for future discoveries.

“Repeated P. falciparum infections drive the development of clinical immunity to malaria in humans; however, the immunological mechanisms that underpin this response are only partially understood. We investigated the impact of repeated P. falciparum infections on human γδ T cells in the context of natural infection in Malian children and adults, as well as serial controlled human malaria infection (CHMI) of U.S. adults, some of whom became clinically immune to malaria,” the investigators wrote.

“In contrast to the predominant Vδ2+ T cell population in malaria-naïve Australian individuals, clonally expanded cytotoxic Vδ1effector T cells were enriched in the γδ T cell compartment of Malian subjects. Malaria-naïve U.S. adults exposed to four sequential CHMIs defined the precise impact of P. falciparum on the γδ T cell repertoire. Specifically, innate-like Vδ2+ T cells exhibited an initial robust polyclonal response to P. falciparum infection that was not sustained with repeated infections, whereas Vδ1+ T cells increased in frequency with repeated infections.

“Moreover, repeated P. falciparum infection drove waves of clonal selection in the Vδ1+ T cell receptor repertoire that coincided with the differentiation of Vδ1naïve T cells into cytotoxic Vδ1effector T cells. Vδ1+ T cells of malaria-exposed Malian and U.S. individuals were licensed for reactivity to P. falciparum parasites in vitro. Together, our study indicates that repeated P. falciparum infection drives the clonal expansion of an adaptive γδ T cell repertoire and establishes a role for Vδ1+ T cells in the human immune response to malaria.”

“Our findings that gamma delta T cells are an important component of an effective immune response to malaria will be very important for the development of future vaccines,” said Anouk von Borstel, PhD, a postdoc research fellow in the lab of Martin Davey, PhD, senior research fellow and first author of the paper. “Gamma delta T cells are not very well understood, and our findings show that the gamma delta TCR is critical to their response to malaria which will open new areas to harness these cells for infectious diseases.”

“These cells have long been thought to be involved in immunity to malaria, but their potential role and how they do this has not been elucidated. This international study provides a breakthrough in our understanding of gamma delta T cell immunity and evidence for their vital importance in combating infectious pathogens,” added Davey.

“These are important T cells that form a major component of the immune response to malaria. With a greater understanding of how our immune system operates in response to infectious disease, we can reveal crucial factors that can be delivered by next-generation vaccines.”