Cold or COVID-19? Some T cells are ready to fight both

Scientists at the La Jolla Institute for Immunology (LJI) have found direct evidence that exposure to cold coronaviruses can train T cells to fight SARS-CoV-2. In fact, prior exposure to a cold coronavirus appears to partially protect mice from lung damage during subsequent SARS-CoV-2 infection.

The new research, published recently in Natural communications, provides an important first insight into how “cross-reactive” T cells, capable of fighting multiple viruses from the same family, develop in an animal model. “We are learning how these immune cells develop and function,” says study co-leader Annie Elong Ngono, Ph.D., an LJI research instructor.

The Shresta laboratory is currently working on the development of new vaccines specially designed to exploit these powerful T lymphocytes. These vaccines would protect against SARS-CoV-2 and provide immunity against several other coronaviruses with pandemic potential.

“Our research will help scientists design and improve ‘pan-coronavirus’ vaccines that elicit broad, cross-protective responses,” adds LJI Professor Sujan Shresta, Ph.D., lead study leader and member from the LJI Center for Vaccine Innovation.

How powerful are T cells?

T cells tend to be specialists. They learn to track specific molecular targets, called epitopes, that belong to specific pathogens. “Cross-reactive” T cells are important to human health because they recognize epitope targets on different, but closely related, pathogens, such as different members of the coronavirus family. This viral family includes common cold coronaviruses and serious pathogens such as SARS-CoV-2.

The COVID-19 pandemic has put cross-reactive T cells in the spotlight. In early 2020, LJI professors Shane Crotty, Ph.D. and Alessandro Sette, Dr.Biol.Sci., discovered that many people, who had never been exposed to SARS-CoV-2, already had T cells that recognized the new virus. corona virus. How did these T cells know what to look for?

SARS-CoV-2 only emerged in 2019, but many people had contracted cold coronaviruses long before then. LJI scientists showed that cross-reactive T cells could recognize targets on both viruses. In follow-up studies, researchers even found an association between cross-reactive T cells and a lower risk of developing severe COVID-19.

If T cells could learn to target both viruses at once, scientists could perhaps design a vaccine against many types of coronaviruses, including new variants of SARS-CoV-2. That was the hope, but there was still much to learn.

“To design better vaccines, we need to know exactly how these protective T cells develop and how long this window of protection lasts,” says Rúbens Alves, Ph.D., a postdoctoral researcher at LJI, who was first author of the new study.

The Shresta Lab strives to answer these questions. Lab members specialize in the development of humanized mouse models, allowing them to study infectious diseases and immune cell responses relevant to humans in a controlled environment.

Cross-reactive T cells to the rescue

For the new study, the researchers used strains of mice capable of producing exactly the same variety of T cells as those found in humans. The researchers infected these mice with one of the most common cold coronaviruses, called OC43. Both SARS-CoV-2 and OC43 are betacoronaviruses.

Scientists found that mice infected with OC43 produced CD4⁺ “Helper” T cells and CD8⁺ “Killer” T cells that cross-reacted with SARS-CoV-2. These cells targeted the same epitopes as T cells collected from humans exposed to SARS-CoV-2.

Next, the researchers developed a sequential infection model – with OC43 infection followed by SARS-CoV-2 in these humanized mice. They examined whether cross-reactive T cells actually helped protect mice against severe forms of COVID-19.

Cross-reactive CD4⁺ The “helper” T lymphocytes indeed helped to thwart the virus’s assault on the respiratory system. Mice with previous exposure to OC43 had lower levels of SARS-CoV-2 infection in their respiratory tract and were less likely to develop pneumonia and lung damage. Cross-reactive T cells have really helped prevent serious illness.

“Our laboratory’s expertise in mouse models has allowed us to delve deeper into what human studies suggest,” explains Elong Ngono.

Next steps for vaccine design

SARS-CoV-2 is not the first coronavirus to cause a deadly outbreak. SARS, which caused a deadly outbreak in 2003, was also a coronavirus. MERS too. This new study is an important step in understanding how T cells might learn to recognize and respond simultaneously to many coronaviruses, including emerging variants of SARS-CoV-2 and other family members exhibiting pandemic potential.

In the future, the team would like to study how exposure to other types of cold coronaviruses affects T cells. Will cross-reactive T cells continue to grow? Would they want to look for the same shared epitopes or different targets?

“We now have the mouse model to study different human infection scenarios, such as the common situation in which a person has been infected several times with different cold coronaviruses before encountering SARS-CoV-2,” says Shresta. “We now even have a model to characterize different relevant human T cell responses elicited by the SARS-CoV-2 vaccine and determine the contribution of these T cells to vaccine-induced protection.”

Shresta says the Institute is well equipped to move forward with this pandemic prevention research. She credits LJI for ensuring that LJI scientists have the training and facilities essential for infectious disease research. Shresta also points out that philanthropic support allowed the Institute to build a Biosafety Level 3 laboratory for this critical study, as well as many others.

Additional authors of the study, “CD4 caused by the common cold coronavirus⁺ T cells protect against SARS-CoV-2 in HLA transgenic mice”, including Julia Timis, Robyn Miller, Kristen Valentine, Paolla Beatriz Almeida Pinto, Andrew Gonzalez, Jose Angel Regla-Nava, Erin Maule, Michael N Nguyen, Norazizah Shafee, Sara Landeras Bueno, Eduardo Olmedillas, Brett Laffey, Katarzyna Dobaczewska, Zbigniew Mikulski, Sara McArdle, Sarah R. Leist, Kenneth Kim, Ralph S. Baric, and Erica Ollmann Saphire.