Persistent immune memory of COVID-19 found in recovered patient T cells

Oxford University researchers have found that natural infection with COVID-19 produces a robust T cell response, including inducing T cell ‘memory’ to potentially fight future infections. The results, published in Nature Immunology, are a joint effort from the Oxford COVID-19 immunology group, led by the Medical Research Council Human Immunology Unit at the MRC Weatherall Institute of Molecular Medicine and the Chinese Academy of Medical Science Oxford Institute at the University of Oxford.

While research has shown that COVID-19 induces a B cell antibody response, it has been less clear whether COVID-19 causes the immune system to make virus-specific T cells too, and whether they are important for recovery from the initial infection, and protection against new infections.

While antibodies latch onto and destroy disease-causing agents like viruses and bacteria, T cells latch on to diseased cells within the body, such as tumour cells or virus-infected cells. T-cells also help attract other immune cells to the area.

Study lead Professor Tao Dong from the MRC Human Immunology Unit said: “By studying the T cell immune response in depth and breadth, we will begin to build a better understanding of why some individuals develop milder disease, and how we might be able to prevent or treat infections.

“T cells may also be longer lasting than antibodies, and so could offer alternative methods to diagnose whether someone has had a past COVID-19 infection, after antibody levels have waned.”

T cells are attracted to tumour or viral protein fragments (called epitopes) displayed on the surface of diseased cells, which act like waving a flag to the T cells, showing them where they are needed.

In this study, the researchers analysed blood samples from COVID-19 patients to identify peptides containing T cell epitopes, including six immunodominant regions (epitope clusters) that were targeted by T cells in many of the patients.

Professor Dong, who is also the Founding Director of the Chinese Academy of Medical Sciences Oxford Institute (COI) based at the Nuffield Department of Medicine, University of Oxford, added “By identifying regions of the virus that are targeted by the immune system, we anticipate the findings will help define the role of T cells in disease outcomes."

The research team compared blood samples from 28 mild and 14 severely ill COVID-19 patients, as well as samples from 16 healthy donors.

Study co-lead Professor Graham Ogg, Interim Director of the Medical Research Council Human Immunology Unit said: “We found that individuals with mild COVID-19 had a different pattern of T cell response when compared to those with more severe infection; this could help provide insights to the nature of immune protection.”

While research team think that a poor quality T cell response might contribute to SARS-CoV-2 viral persistence and COVID-19 mortality, recovered patients with mild as well as severe disease still had T cell memory two months after infection.

Only a small number of T cells need to have a memory of the primary infection, and they can replicate to mount a robust immune response quickly.

The researchers also found that the spike protein of SARS-CoV-2 was often recognised by T-cells from recovered patients, which adds support for the approaches used by many of the current vaccines in development, including the Oxford vaccine. The research team additionally found that other parts of the virus, including its membrane and its nucleoprotein, also provoked a strong T cell immune response, potentially providing other vaccine targets too.

Professor Ogg, who is a working clinician as well as a researcher at the University of Oxford Radcliffe Department of Medicine added “The research demonstrates the power of bringing together many clinicians and scientists to address a global challenge, and we are extremely grateful to all of those involved, especially the research participants.”

The team now plan to investigate how long T cell immune memory lasts and whether this might have implications for novel diagnostic tests and new treatments.

Expert comments

Medical Research Council Executive Chair Professor Fiona Watt said: “The results of this research come at a critical time because they increase our knowledge of the role T cells play in the body’s immune response to infection with COVID-19. This knowledge can inform the design of future vaccines to protect us from the virus. It demonstrates that long-term investment in institutions like the MRC’s Human Immunology Unit pays dividends that cannot always be predicted.”

Sir John Bell, Regius Professor of Medicine at the University of Oxford, said: “This is a very important paper that establishes the importance of T cell responses to COVID infections. Many of the puzzles associated with this disease may be solved with a better understanding of this arm of the immune response and this paper establishes the basis on which those studies can occur.”

The University of Birmingham’s Professor Paul Moss, who leads the UK Coronavirus Immunology Consortium, commented, “This paper is highly important in the fight against SARS-CoV-2. The team demonstrate that cellular immune responses develop in most people after infection and are particularly strong in those with more severe disease. In addition they show that T cells are able to recognise many different proteins within the virus and identify strong target regions that are shared between different people. This provides the foundation for new approaches to assess immunity and also for optimisation of vaccine design."

Professor Peter Openshaw from Imperial College London, Immunology Lead for UK ISARIC - Coronavirus Clinical Characterisation Consortium said “It is exciting to see the speed with which UK scientists can generate such novel findings and the spirit of collaboration that underpins it. T cells are important in clearing the virus and recognise parts of SARS-CoV-2 that are not seen by antibody. The role that they play in disease is not yet fully revealed, but this study provides the tools for studies to be done. This landmark study opens many new areas of work.“

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