Superantigens – The Immune System Meets Microbes

Our immune system is fine-tuned to respond to a variety of different antigens, but some pathogens have found a way to hijack the immune system.

Several bacterial species, most notably Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes), as well as some viruses, release superantigens: a type of toxin capable of over-activating the immune system. There are at least 25 superantigens known to date, and some have been linked to severe effects of bacterial infections, such as toxic shock syndrome.

Since the 1980s, toxic shock syndrome is often thought of as a side effect of tampon use, but it can occur after any infection with a superantigen-producing bacterium. Superantigens are also responsible for the development of rheumatic fever and rheumatic heart disease after infection with S. pyogenes.

How do superantigens manipulate the immune system into causing such extreme reactions? And what other secrets do they hide?

Superantigens mislead the immune system

Superantigens interfere with the adaptive immune system. In the absence of superantigens, the system works as follows: Antigen-presenting cells, such as dendritic cells and phagocytes, take up extracellular pathogens and process their proteins into individual antigen fragments, which are then displayed on the outside of the cell by the major histocompatibility complex II (MHC-II). The antigen-carrying MHC-II complex is then recognized by receptors on circulating T cells.

These T-cell receptors (TCR) are normally quite specific to certain MHC-II/antigen combinations, and only need to bind very briefly for the T cell to be activated and initiate the immune response. In a normal immune response, only about 0.001 % to 0.01 % of all T cells are activated.

But a superantigen kicks off an entirely different process. Superantigens are not processed by the antigen-presenting cell. Instead, they bind directly to the outside of the MHC-II. Meanwhile, another binding site on the superantigen interacts with the Vβ subunit of the TCR. By bridging the TCR and MHC-II, superantigens put these complexes in contact with each other for much longer than normal. It’s also a less specific process than a normal antigen-specific immune response. As a large fraction of the T cells have a Vβ subunit in their receptor, around 20 % of T cells can be activated when a superantigen connects them to MHC-II.

These activated T cells release a large number of cytokines, such as interleukin-2 (IL-2), interferon-γ (INF-γ) and tumor necrosis factor α (TNF-α). This cytokine storm is what causes toxic shock syndrome, rheumatic fever, and other extreme symptoms experienced as a consequence of some bacterial infections.

Beyond the cytokine storm

Why do bacteria such as S. aureus and S. pyogenes produce these superantigens?

“It doesn't make sense for bacteria to produce toxins that would essentially kill their host,” says John McCormick, Professor in the Department of Microbiology and Immunology at Western University in Canada. “It seems counterintuitive that these bacteria, that spend an awful lot of effort trying to hide from the immune system, also make these toxins that activate the immune system.”

And indeed, it’s becoming increasingly clear that superantigens play other roles as well.

“One of the biggest misconceptions in the field of superantigens is that causing cytokine storms is all they do,” says Wilmara Salgado-Pabón, Assistant Professor in the Department of Pathobiological Sciences at the University of Wisconsin – Madison. “We're so stuck on the cytokine storm, that we've completely missed the many roles that those toxins can play in multiple diseases.”

Only three of the known superantigens are associated with toxic shock syndrome, and Salgado- Pabón is interested in finding out what the purposes of the other known toxins are. So far, it appears that specific superantigens can have a local effect on infected tissues. For example, upon S. aureus infection, some superantigens contribute to local tissue pathology in the development of infective endocarditis.

“What we're finding is that superantigens are multi-functional. Yes, they can activate the immune system, but they can also dysregulate or manipulate every other tissue that they come in contact with or interact with.”

Essentially, superantigens are doing more than just hijacking our immune system. They need to be viewed as any other pathogenic toxins – and that opens up entirely new research areas.

Superantigens as potential vaccine candidates

If you’ve been infected with one of the strains that produce superantigens, you will start to produce antibodies against them. But not everyone builds up this protective immunity in the same way.

In a study published earlier this year, researchers at the La Jolla Institute for Immunology and the University of California, San Diego, found that children with a recurrent form of tonsillitis had fewer antibodies against the S. pyogenes superantigen SpeA.

“We wanted to further explore that, so we looked at the germinal center T follicular helper (Tfh) cells in the tonsils of children with recurrent tonsillitis,” says infectious disease specialist and Clinical Associate Jennifer Dan, who was first author on this study.

Tfh cells are a type of CD4+ cell that help provide instructions for the antibody response, and Dan was curious how these cells responded to S. pyogenes infection. “We found that SpeA induced higher frequencies of cytolytic Tfh cells in children with recurrent tonsillitis. Instead of helping B cells, these aberrant Tfh cells kill B cells.”

Meanwhile, children who did not have recurrent tonsillitis, but who had been exposed to S. pyogenes, had higher levels of antibodies against SpeA, and their tonsils had larger germinal centers overall. Overall, this suggests that the immune response to SpeA affects the course of the disease.

McCormick’s group also found a role for SpeA in establishing S. pyogenes infection. In studies in mice expressing human MHC-II, they showed that SpeA was required for infection to establish. In a follow-up study, McCormick’s group showed that by vaccinating these transgenic mice with a deactivated form of SpeA, they started producing antibodies against SpeA. These mice became less susceptible to infection with SpeA-producing S. pyogenes. The same was seen in mice that were directly injected with anti-SpeA antibodies, showing that SpeA was required for colonization and infection.

This not only showed that superantigens have a function beyond attacking their host’s immune system, but it also paves the way for research into the use of SpeA as a possible vaccine to strengthen the immune response against S. pyogenes infection.

“S. pyogenes is a massive global problem, particularly for patients who develop rheumatic heart disease,” says McCormick. “This often targets lower income countries and communities with fewer resources, but there's no vaccine yet for S. pyogenes.”

It’s still early days for superantigens as vaccine candidates, but it illustrates the shift in attention that these molecules have received in the last few decades. Even though superantigens were initially named for their role as a virulence factor, there is a lot more to them, and many of their secrets have yet to be uncovered.