The virus responsible for the COVID-19 pandemic, SARS-CoV-2, is part of a large family of coronaviruses. Coronaviruses usually cause mild to moderate upper-respiratory tract illnesses, like the common cold. However, SARS-CoV-2 can cause serious illness and even death. Why people’s COVID-19 symptoms vary so greatly isn’t fully understood.

Your body’s disease defense system, the immune system, makes B and T cells when exposed to pathogens like viruses and bacteria. B cells make antibodies, which neutralize the microbes, rendering them harmless. T cells have a variety of functions, including killing infected cells and activating or recruiting other immune cells.

Once your body fends off a microbe, it retains some disease fighting cells as memory cells. The next time you’re exposed to it, a memory cell is ready to fight the disease again. This gives your immune system a head start in combating the disease.

Previous studies have reported that 20–50% of people who hadn’t been exposed to SARS-CoV-2 showed T cell responses against different parts of the SARS-CoV-2 virus. To investigate further, a research team led by Drs. Alessandro Sette and Daniela Weiskopf at the La Jolla Institute for Immunology tested blood samples collected between March 2015 and March 2018 for T-cell responses against different pieces of SARS-CoV-2. The work was funded by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Results were published on August 4, 2020 in Science.

The team first tested the volunteers’ T cells for responses against several pools of peptides—the short stretches of amino acids that make up proteins. Each peptide consisted of 15 amino acids from SARS-CoV-2. Cells that showed a response to a pool of peptides were then tested again against a pool of peptides spanning the spike protein (the part of the virus that latches onto human cells) or pools of 10 peptides each that spanned the non-spike regions of the virus. The team screened 474 SARS-CoV-2 peptides total.

The team narrowed the pools until they identified 142 fragments of the virus that interacted with the T cells—66 from the spike protein and 76 from non-spike regions. Of these, 40 were recognized by T cells from two or more donors. These fragments might prove useful for COVID-19 vaccine trials and tracking memory T cells during infection.

The researchers generated T cell lines from the memory cells that recognized SARS-CoV-2 fragments. They then tested them for cross-reactivity against a peptide pool from other coronaviruses. They found that of the SARS-CoV-2 and “common cold” coronavirus fragments that were most similar (at least 67% genetic similarity) 57% showed cross-reactivity by memory T cells.

“We have now proven that, in some people, pre-existing T cell memory against common cold coronaviruses can cross-recognize SARS-CoV-2, down to the exact molecular structures,” Weiskopf says. “This could help explain why some people show milder symptoms of disease while others get severely sick.”

“It still remains to be addressed whether this immune memory reactivity influences clinical outcomes and translates into some degrees of protection from more severe disease,” adds Sette. “Having a strong T cell response, or a better T cell response may give you the opportunity to mount a much quicker and stronger response.”

Notably, these findings contrast with those from antibodies, which haven’t shown significant cross-reactivity between common cold coronaviruses and SARS-CoV-2. More research is needed to determine whether immune cell cross-reactivity contributes to the wide range of symptoms seen with COVID-19.

This article was originally published on the NIH website on August 18, 2020.