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Molecular and functional evolution of human CD8+ T cell repertoires

Periodic Reporting for period 1 - TC-Evo (Molecular and functional evolution of human CD8+ T cell repertoires)

Reporting period: 2018-05-01 to 2020-04-30

During our life-time, we encounter many pathogens (infectious agents like viruses and bacteria). The immune system is our main defence mechanism to prevent us from getting sick. One of the main 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 can detect and clear these pathogens in a highly specific manner. In other words, when you get infected with for example an influenza virus your adaptive immune system comes into action, but only activates those immune cells that are able to recognize this particular influenza virus strain. However, 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. CD8+ killer T cells have special receptors on their cell surface, the so-called T cell receptors (TCRs), which enables them to recognize virus infected cells in a highly specific manner. Once they recognize an infected cell, they can kill this cell before it makes new viruses that could infect other cells (Figure 1). Previous research on CD8+ killer T cells mainly focused on their function in adults (adults are known to have excellent and very specific CD8+ killer T cells), and some studies were done in elderly. However, research that focuses on how these CD8+ killer T cells develop during childhood are non-existent. Studying the CD8+ 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 will take place at the University of Melbourne in Australia and focuses on answering the overarching aim of this project using the most recent and ground-breaking technology to study CD8+ killer T cell responses in the greatest detail as possible.

The second part of the Tc-Evo project will take place at Sanquin in the Netherlands. The aim of this second part is to implement this new ground-breaking technology at a European research institute, while focusing on a slightly different cell type. Recent evidence has highlighted the importance of CD8+ killer T cells in the lung (so called tissue resident T cells) to protect against severe respiratory infections (like influenza). What determines the fate of a CD8+ killer T cell to stay in the lung for a rapid and strong immune response upon re-infection is currently unknown. Tc-Evo aims to define what determines the fate of a CD8+ killer T cells to become tissue resident.

Importance: Fundamental knowledge on how or immune system develops while aging is especially relevant given our aging 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 localized immune memory response while retaining some flexibility in order to cope with new/slightly different pathogenic infections. For example, a single influenza vaccine that gives long-lasting protection against seasonal and pandemic influenza viruses.
Outgoing phase:
Research:
- Establishment of a biobank for the specific research outlined in the MSCA fellowship
- Gathered data and analysis to compare and contrast magnitude, phenotypic and functional characteristics, TCR repertoires and functionality and molecular and profiles across different age groups
- The unique skills and samples collected for this project resulted in multiple collaborations with scientist within the Doherty Institute and beyond. Several of the collaborations have already resulted in publications (see below) and include work on the current COVID-19 pandemic.

Main achievements:
- 7 scientific publications in peer-reviewed journals (including one first and one senior authorship)
- 8 presentations at (inter-)national conferences (including two invited speaker presentations)
- 3 travel/network awards
- Research is covered by >200 news outlets worldwide
- Organizer Respiratory Research Seminars at the Doherty Institute
- Organizer COVID19 seminal and panel discussion at the Doherty Institute
- Supervisor of honours student
- Chair of minisymposium and workshop at the 17th International Congress of Immunology, IUIS 2019 in China
- Participated in 6 public outreach events including a documentary, research blogs, the science nation and science week
- Participated in 6 trainings/workshops
The result from the present study are highly relevant not only scientifically but also clinically and touch upon a socially hot topic. Seasonal influenza virus infections result in a major economic burden each year (time lost from work absenteeism, hospitalization 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, disease severity and mortality during the COVID-19 pandemic 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 for advancements in vaccine development. 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 identification of 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 for the influenza community but also to other research communities. Hence, a superior immunity in school-aged children is also observed in other infectious diseases, including mumps, measles, VZV, EBV, HEV and even SARS-CoV1 and SARS-CoV2. Finally, advancing our knowledge in 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