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Immune system’s T cells can mount attacks against many coronavirus targets — even on new variants, LJI says

An electron micrograph shows SARS-CoV-2 particles isolated from a patient.
An electron micrograph shows SARS-CoV-2 particles isolated from a patient.
(National Institute of Allergy and Infectious Diseases)

A new study led by scientists at the La Jolla Institute for Immunology suggests that T cells try to fight SARS-CoV-2, the coronavirus that causes COVID-19, by targeting a broad range of sites on the virus. By attacking the virus from many angles, the body has the tools to potentially recognize different SARS-CoV-2 variants.

An increase in social contact, a UCSD modeler warns, could be just the thing to cause infection rates to explode as the strain achieves dominance.

The new research, published Jan. 27 in Cell Report Medicine, is the most detailed analysis so far of which proteins on SARS-CoV-2 stimulate the strongest responses from the immune system’s “helper” CD4+ T cells and “killer” CD8+ T cells.

“We are now armed with the knowledge of which parts of the virus are recognized by the immune system,” said LJI professor Alessandro Sette, who co-led the study with LJI instructor Alba Grifoni.

Sette and Grifoni have led research into immune responses to the virus since the beginning of the pandemic. Their previous studies, co-led by members of the LJI Coronavirus Task Force, show that people can have a wide range of responses to the virus — some have strong immune responses and do well; others have disjointed immune responses and are more likely to end up in a hospital.

As COVID-19 vaccines reach more people, LJI scientists are keeping an eye on how different people build immunity to SARS-CoV-2. They also are studying how T cells could combat different variants of SARS-CoV-2. This work takes advantage of the lab’s expertise in predicting and studying T cell responses to viruses such as dengue and Zika.

“This is even more important with COVID-19 because it is a global pandemic, so we need to account for immune responses in different populations,” Grifoni said.

The immune system is very flexible. By re-scrambling genetic material, it can make T cells that respond to a huge range of targets, or epitopes, on a pathogen. Some T cell responses will be stronger against some epitopes than others. Researchers call the targets that prompt a strong immune response “immunodominant.”

For the new study, the researchers examined T cells from 100 people who had recovered from SARS-CoV-2 infection. Their analysis revealed that not all parts of the virus induce the same strong immune response in everyone.

The study shows that while the immune system often mounts a strong response against a particular site on the virus’ “spike” protein called the receptor binding domain, this region is actually not as good at inducing a strong response from CD4+ helper T cells.

Without a strong CD4+ T cell response, however, people may be slow to mount the kind of immune response that quickly wipes out the virus. But most people have immune cells that can recognize sites other than the receptor binding domain.

Among the many epitopes they uncovered, the researchers identified several additional epitopes on the SARS-CoV-2 spike protein. Grifoni said that is good news. By targeting many vulnerable sites on the spike protein, the immune system would still be able to fight infection, even if some sites on the virus change due to mutations.

“The immune response is broad enough to compensate for that,” Grifoni said.

Since the announcement of the fast-spreading U.K. variant of SARS-CoV-2, the researchers have compared the mutated sites on that virus with the epitopes they found. Sette said the mutations described in the U.K. variant for the spike protein affect only 8 percent of the epitopes recognized by CD4+ T cells in this study, while 92 percent of the responses are conserved.

Sette said the new study is the result of months of long hours and international collaboration among researchers at LJI, UC San Diego and Australia’s Murdoch University.

— La Jolla Light staff contributed to this report.