Messenger protein could potentially boost vaccine performance

Interleukin-21
Immune response following vaccination - follicle showing germinal centre (Bcl6, cyan), naive B cells (IgD, red) and antigen specific T (CD45.2, blue) and B cells/plasma cells (GFP, green) Image: Isaak Quast

A study by Monash University researchers has revealed the way a protein important in immune cell signalling can amplify the immune response, which could potentially benefit vaccine design.

The study, led by Department of Immunology and Pathology scientists Professor David Tarlinton and Dr Isaak Quast, is now published in the prestigious journal Immunity.

It identified, in animal models, specifically how the messenger cytokine Interleukin-21 (IL-21) works on the T cells and B cells involved in the body’s immune response.

Successful vaccination relies on the coordinated behaviour of immune cells and typically results in the production of antibodies, specialised proteins that recognise and fight invading pathogens such as viruses. Interleukin-21, which occurs naturally in the body, is a key component of this process.

“We identified that this messenger IL-21 works on the cells that produce it as well as the other cells in the immune response,” Professor Tarlinton said. “It’s a so-called autocrine factor for T lymphocytes – they make it and also respond to it, which is important to increasing their numbers and activity,” he said.

Cell bath cartoon
T cell universally delivering IL-21 to B cells participating in the response. Cartoon by Jakob Quast

“What Isaak also found was that it acts on B lymphocytes in a general way – it is produced as part of the interaction between two cells, but it actually affects cells in the surrounding areas as well, making them more receptive to any additional help and to responding by proliferating and differentiating.”

The magnitude of the initial response to vaccination and its subsequent maintenance was vital in determining – and potentially benefiting – the generation of protective antibody responses, the researchers said.

“Our recent work found that the cytokine IL-21 is a key component of this process by establishing a feed-forward loop,” Dr Quast said. “The cells that produce the cytokine can help neighbouring cells become cytokine-producing cells. These T cells are amplified and then stimulate the B cells. This really sets up the immune response to maintain itself in a very general sense.”

“To separate out what actions IL-21 has on different cells and when, is a big improvement in our understanding of how immune responses are initiated,” Professor Tarlinton said. “In terms of the implications, if you’re designing an immune response you’d like to have IL-21 produced in this way by these cells over this interval to optimise the response.

“One could imagine that in terms of making a vaccine or an immune response, having just the right amount of IL-21 is important to activate the right number of cells to give you a good response without having the potential to recruit and amplify harmful self-reactive cells.”

Ensuring adequate production of IL-21 could offer an avenue to extend the immune response of existing vaccines such as the mRNA vaccines, Professor Tarlinton said.

Dr Quast said that more precisely understanding the mechanisms involved, and the molecular pathways that follow, could potentially lead to developing therapies that either inhibit immunity, for example in the case of auto-immune disease, or promote it in vaccines, he said.

The study builds on more than a decade of work into IL-21 by the scientists and ties into a paper published in EMBO Reports earlier in the month.

Read the full paper in Immunity titled: Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B Cells. DOI: 10.1016/j.immuni.2022.06.020