T-lymphocytes can protect against SARS-CoV-2 variants even in the absence of antibodies

Vaccines have played a crucial role in reducing morbidity and mortality caused by SARS-CoV-2. However, the emergence of new virus variants capable of evading from antibody response raises questions about the long-term effectiveness of this strategy. 

Recent research published in the prestigious journal Nature Immunology opens new perspectives on understanding the immune response against the virus, highlighting the fundamental role of T-lymphocytes as an enduring defense weapon present in our bodies, beyond the antibody-mediated response. 

To investigate this issue, researchers employed several mouse models, including those lacking antibodies but with intact lymphocyte function, and a novel model expressing a hybrid human receptor ACE2/murine. 

The study was coordinated by Professor Matteo Iannacone, director of the Division of Immunology, Transplantation and Infectious Diseases at Ospedale San Raffaele and Professor of General Pathology at University Vita-Salute San Raffaele, and carried out in collaboration with Professors Luca Guidotti, deputy scientific director and Professor of General Pathology at Ospedale San Raffaele and University Vita-Salute San Raffaele, Marco Bianchi, head of the Chromatin Dynamics Unit at Ospedale San Raffaele and Professor of Molecular Biology at University Vita-Salute San Raffaele, and Raffaele De Francesco, head of the Virology Laboratory at the National Institute of Molecular Genetics and Professor of Microbiology at the University of Milan.

When our immune system is affected by an infection, it puts in place several defense mechanisms, including: 

• activation of B-lymphocytes, which are deputed to produce antibodies;
• activation of T-lymphocytes, which coordinate the entire immune system, defeating cells identified as “foreign” and therefore potentially harmful.

“Our research revealed that T-lymphocytes, due to their historical memory, are able to provide protection against SARS-CoV-2 virus even when antibodies are not present. This antibody-independent form of defense empathizes the crucial significance of the T-cell-mediated cellular response in the fight against the virus,” says Professor Matteo Iannacone. 

“Our observations show that a certain subset of T-lymphocytes, called CD8+, is crucial in countering severe infections, while the so-called CD4+ T-lymphocytes play a complementary role in milder infections, with a significant role played by interferon-gamma (IFN-γ),” adds Dr. Valeria Fumagalli, a researcher in Prof. Iannacone's laboratory, first author of the study, and recipient of a specific grant from the Prossimo Mio Foundation in Milan.

Until now, the SARS-CoV-2 defense strategy has mainly emphasized the antibody response, assuming that the antibody-mediated response is the main, if not the only, mechanism of protection after vaccination or contact with the virus. 

"The results of our study change the traditional understanding of immunity and demonstrate the importance of including the T-cell-mediated immune response in monitoring responses to vaccination and in strategies for developing new vaccines," Professor Iannacone emphasizes. – 

“The indication for vaccination remains the key element in protecting the population from serious disease, and our research demonstrates the effectiveness of this approach also for protection against reinfection caused by viral variants."

"This work highlights the importance of an approach to immunity against SARS-CoV-2 that considers both antibody and cellular responses. Our research paves the way for new vaccine and therapeutic strategies for effective and long-lasting protection against the virus and its emerging variants," adds Professor Iannacone.

"The study was possible thanks to the continued support of the SAME Foundation, a philanthropic entity of the Same Deutz Fahr Group, in Treviglio," Professor Luca Guidotti points out.– 

SAME Foundation enabled the construction and set-up of BSL3 biosafety environments, the only one of their kind in Italy, at IRCCS Ospedale San Raffaele; thanks to the various advanced technologies dedicated to the study of high-threat respiratory viruses in mouse models, these environments have enabled and continue to enable the conduct of high-precision research on SARS-CoV-2," Professor Luca Guidotti continues. 

Among the innovative research tools used in this project, thanks to donations, is an inhalation tower that allows mouse models to be exposed to viral particles, infecting them physiologically by exposure to aerosolized SARS-CoV-2 under pressure, temperature and humidity. 

"SAME Foundation's support is yet another example of how scientific research in Italy benefits enormously from high-impact philanthropic activities," Professor Guidotti concludes.