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Molecular and functional evolution of human CD8+ T cell repertoires

Periodic Reporting for period 2 - TC-Evo (Molecular and functional evolution of human CD8+ T cell repertoires)

Reporting period: 2020-05-01 to 2021-04-30

During our life-time, we encounter many pathogens (infectious agents like viruses). The immune system is our main defence mechanism to prevent us from getting sick. One of the key players is adaptive immunity (including T cells), which gets its name from is ability to change and adapt depending on the pathogen you encounter. T cells detect and clear these pathogens in a highly specific manner. In other words, when you get infected with an influenza virus your adaptive immune system comes into action, but only activates those immune cells that are able to recognise this particular influenza virus strain. The initial response upon the first encounter with a pathogen is relatively slow. An important feature of the adaptive immune system is that it remembers the pathogen you encountered. This immunological memory enables your immune system to respond faster and stronger when you get re-infected with the same pathogen. This way your immune system prevents you from getting sick a second time. It is not fully understood how our immune response develops (children), maintains (adults) and loses (elderly) memory and strong functionality over the years.

TC-Evo’s overarching aim: To gain fundamental knowledge on how our immune system develops during immunologically-distinct phases of our life, from birth to old age.

Tc-Evo focuses on a specific part of the adaptive immune system, the so called CD8 T cells, also known as killer cells. Killer T cells have special receptors on their cell surface, the T cell receptors (TCRs), which enables them to recognise virus infected cells in a highly specific manner. Once they recognise an infected cell, they can kill this cell before it makes new viruses that could infect other cells (Figure 1). Previous research on killer T cells mainly focused on their function in adults (adults are known to have excellent and very specific killer T cells), and some studies were done in elderly. However, research that focuses on how these killer T cells develop during childhood are non-existent. Studying the killer T cell response in children is of special interest as children cope exceptionally well with novel virus infections. Not only are children able to form a strong memory response, their ability to recover from novel virus infections is superior to that of other age groups (Figure 2).

The first part of the Tc-Evo project took place at the University of Melbourne in Australia and focused on answering the overarching aim of this project using the most recent and ground-breaking technology to study killer T cell responses in the greatest detail as possible.

The second part of the Tc-Evo project took place at Sanquin in the Netherlands. The aim of this second part was to implement this new ground-breaking technology at a European research institute, while focusing on a slightly different cell type. Due to COVID-19, this part was revised to study COVID-19 specific immunity after infection and vaccination in high-risk groups including autoimmune patients.

Importance: Fundamental knowledge on how or immune system develops while ageing is especially relevant given our ageing population and is likely to contribute to new therapies against a wide variety of diseases. Furthermore, the Tc-Evo research project is likely to give new insights on how to develop new vaccines strategies that train our immune system to develop stronger localised immune memory response while retaining some flexibility in order to cope with new/slightly different pathogenic infections. For example, a single vaccine that gives long-lasting protection against seasonal and pandemic viruses.
Outgoing phase:
- Establish an ageing-cohort
- Experiments to compare and contrast magnitude, phenotype, functionality, TCR repertoires and molecular profiles across human lifespan
- Unique skills & ageing cohort resulted in multiple collaborations resulting in several publications include on COVID19

Main achievements:
- 15 scientific peer-reviewed publications (3x first & 2x senior author)
- 9 presentations at (inter-)national conferences (2x invited)
- 3 travel/network Awards
- 1 collaborative COVID19 research grant
- Research covered by >200 news outlets worldwide (>70 countries, reached >2.6 billion people)
- Organizer Respiratory Research Seminars
- Organizer COVID19 seminar & panel discussion
- Supervised 1 honours student to completion
- Chair of minisymposium & workshop at the 17th ICI/IUIS 2019 in China
- Participated in 8 public outreach events: COVID19 documentary (Broadcast 13/07/2021 ABC Australia), podcast, research blogs, Science nation events & science week
- 7 courses/training/workshops

Returning phase:
- Deviation WP4: Work on tissue resident CD8 T cells could not be carried out due to COVID19 limitations. Instead focussed on 2 studies
- Predicted novel SARS-CoV2 CD8 T cell peptides across 11 HLAs
- Experiments to compare & contrast magnitude & phenotypes of SARS-CoV2 specific T cells longitudinally across disease severity, age, sex
- Deep-immune profiling using whole blood analysis of COVID19 vaccine samples (>500)

Main achievements:
- Established new collaborations: Prof van Ham, Dr. Gisbergen, ten Brinke, Verstegen.
- Supervisor of a PhD student & research assistant
- Co-supervisor of the Sanquin COVID-19 vaccination team (1 Postdoc, 3 Phd students, 3 Research assistants, 1 master student) fully trained for whole blood stain & other immuno-virological techniques
- Participated in 1 public outreach event
Results from the present study are highly relevant scientists, clinicians and the general public as they touch upon a socially hot topic. Seasonal influenza virus infections result in a major economic burden each year (time lost from work absenteeism, hospitalisation and premature death), this burden rapidly increases during a pandemic outbreak as we now experience during the COVID-19 pandemic. As with seasonal and pandemic influenza infections, COVID-19 disease severity and mortality differs across human lifespan.

A better understanding of the functional and molecular mechanisms that underlie gain- and loss-of-immune function across human life, especially the mechanisms that underlie the superior immunity in children aged 4-15, will open avenues to improve vaccine efficacy. The anticipated results will help us to understand and overcome technical challenges of developing broad-protective vaccines (e.g. selection of effective CD8+ T cell epitopes and/or timing and/or route of vaccination). Furthermore, the results from this study will help predict disease severity and identify high-risk groups, which will allow clinicians to develop cost-effective intervention and treatment strategies during seasonal and pandemic outbreaks (e.g. distributing limited vaccine batches among those most at risk).

The outcome of this study will not only be of interest beyond the influenza research community. A superior immunity in school-aged children is also observed in other infectious diseases, incl. mumps, measles, VZV, EBV, HEV, SARS-CoV1 and SARS-CoV2. Finally, advancing our knowledge on what drives gain- and loss-of-immune function will also be beneficial to other research fields, like tumour immunology.
Figure 1 Virus infected cell recognized by CD8 killer T cell
Figure 2 Aging and immunity