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. Prior exposure to a cold coronavirus appears to partially protect mice from lung damage during a subsequent SARS-CoV-2 infection.
The new study, recently published in Nature Communications, provides important insight into the development of „cross-reactive“ T cells that can combat multiple viruses of the same family in an animal model. „We are learning how these immune cells develop and function,“ says lead author LJI Research Instructor Annie Elong Ngono, Ph.D.
The Shresta Lab is currently working on the development of novel vaccines specifically designed to harness these powerful T cells. These vaccines would protect against SARS-CoV-2 and provide immunity against several other coronaviruses with pandemic potential.
Our research will help scientists develop and improve „pan-coronavirus“ vaccines that elicit broad, cross-protective responses.
– LJI-Professor Sujan Shresta, Ph.D., lead author and member of the LJI Center for Vaccine Innovation
How Powerful Are T Cells?
T cells are usually specialists. They learn to detect specific molecular targets, known as epitopes, belonging to specific pathogens. „Cross-reactive“ T cells are important for human health as they recognize epitope targets on different but closely related pathogens, such as various members of the coronavirus family. This virus family includes cold coronaviruses and severe pathogens such as SARS-CoV-2.
The COVID-19 pandemic has shed light on cross-reactive T cells. 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 novel coronavirus. How did these T cells know what to look for?
While SARS-CoV-2 emerged in 2019, many people had been infected with the cold coronavirus long before. LJI scientists showed that cross-reactive T cells can recognize targets of both viruses. Subsequent studies even found a link between cross-reactive T cells and a reduced risk of severe COVID-19.
If T cells could learn to attack both viruses simultaneously, scientists might be able to develop a vaccine against many types of coronaviruses, including new SARS-CoV-2 variants. This was the hope – but there was still much to learn.
„To develop better vaccines, we need to know exactly how these protective T cells develop and how long this window of protection lasts,“ says LJI postdoctoral fellow Rúbens Alves, Ph.D., who served as the lead author of the new study.
The Shresta Lab is working on answering these questions. Lab members specialize in the development of humanized mouse models, enabling them to examine infectious diseases and human-relevant immune cell responses in a controlled environment.
Cross-Reactive T Cells to the Rescue
For the new study, researchers used mouse strains that can produce the same diversity of T cells as humans. The researchers infected these mice with one of the most common cold coronaviruses called OC43. Both SARS-CoV-2 and OC43 are beta coronaviruses.
The scientists found that OC43-infected mice 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 model of sequential infection – with OC43 infection followed by SARS-CoV-2 in these humanized mice. They investigated whether cross-reactive T cells actually contributed to protecting the mice from severe COVID-19.
Cross-reactive CD4+ „helper“ T cells did indeed help counter the virus’s attack on the airways. Mice with prior OC43 exposure showed lower SARS-CoV-2 infection in their airways and were less likely to develop pneumonia and lung damage. Cross-reactive T cells have truly helped in preventing severe illness.
„The expertise of our laboratory in mouse models has allowed us to delve deeper into the findings of human studies,“ says Elong Ngono.
Next Steps for Vaccine Design
SARS-CoV-2 is not the first coronavirus to cause a deadly outbreak. The 2003 deadly outbreak was also caused by a coronavirus. The same goes for MERS. This new study is an important step in understanding how T cells could learn to recognize and respond to many coronaviruses simultaneously, including emerging SARS-CoV-2 variants and other family members with pandemic potential.
In the future, the team wants to investigate how exposure to other types of cold coronaviruses affects T cells. Will cross-reactive T cells continue to emerge? Would they target the same common epitopes or different targets?
„We now have the mouse model to explore different human infection scenarios, such as the common situation where 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 various human-relevant T cell responses elicited by the SARS-CoV-2 vaccine and to determine the contribution of these T cells to vaccine-induced protection.“
Shresta says the institute is well-positioned to advance this research on pandemic prevention. She commends the LJI for ensuring that its scientists have the necessary training and equipment for the study of infectious diseases. Shresta also highlights that philanthropic support has enabled the institute to establish a biosafety level 3 laboratory for this and many other important studies.
La Jolla Institut für Immunologie
dos Santos Alves, RP, et al. (2024). Durch das menschliche Coronavirus OC43 ausgelöste CD4+-T-Zellen schützen in HLA-transgenen Mäusen vor SARS-CoV-2. Naturkommunikation. doi.org/10.1038/s41467-024-45043-2.