Defining of human adaptive immune gene diversity and its impact on disease

Project Information

IMMUNEDIVERSITY

Grant agreement ID: 788016

DOI

10.3030/788016

Project closed

EC signature date 18 June 2018

Start date 1 December 2018

End date 30 November 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 4 - IMMUNEDIVERSITY (Defining of human adaptive immune gene diversity and its impact on disease)

Reporting period: 2023-06-01 to 2024-11-30

Summary of the context and overall objectives of the project

What is the problem/issue being addressed?
This ERC Advanced project focuses on the genes that encode our adaptive immune receptors, that is our B- and T-cell receptors (BCRs and TCRs). Surprisingly, this area of immunogenetics remains understudied as these genomic regions are not covered by conventional whole genome sequencing approaches. A central goal of this project has been to develop and use specialized sequencing and analysis tools that allow definition of genetic variability in these genes and to apply them to large population groups. In doing so, we can characterize the genetic diversity in BCR and TCR germline genes, both in the form of allelic and copy number variation, resulting in the generation of an improved databases of V, D, and J alleles.

Why is it important for society?
An improved understanding of the genes that encode our TCRs and BCRs is medically highly relevant as adaptive immune responses are central in health and disease. The adaptive immune system is well-known for providing immunological memory, which is the basis for vaccine-induced protection and control of re-infections. However, adaptive immune responses are also involved in numerous other common diseases, including allergy and autoimmune conditions, such as rheumatoid arthritis, multiple sclerosis and diabetes. An improved knowledge about human genetic variability in germline-encoded BCR and TCR V, D, and J genes helps us understand human responses to specific pathogens and provides important information for investigations aimed at understanding the development of immune-mediated diseases. Furthermore, by studying these highly diverse genomic loci, we obtain information that guide studies of human migration and evolution to better understand how we have adapted to external pressures during our history.

What are the overall objectives?
Over the course of this grant period, our work has resulted in the creation of adaptive immune receptor gene databases from thousands of individuals, which we will make publicly accessible upon publication of the studies. We have also developed robust library production protocols for immune receptor (expressed and genomic) sequencing that other immunology laboratory can replicate and we will continue to produce freely accessible software tools that can be installed and used by competent researchers. Furthermore, during this grant period, we have begun to apply these methods to human disease cohorts to investigate if certain adaptive immune receptor gene variants are risk factors for autoimmune diseases.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

An important research output from the ImmuneDiversity project is our paper describing TCR gene diversity in individuals from Africa, East Asia, South Asia, and Europe, where we doubled the number of known TCR gene variants (175 novel alleles) (Corcoran et al. Immunity 2023). In this paper, we also reported the surprising discovery of three Neanderthal-derived TCR regions that are present at high frequencies in modern humans, reflecting introgression events resulting from human migration over the past 60,000 years. We showed that an archaic variant of a gamma V gene generates TCRs with altered function compared to the canonical human allele, and we have since identified additional variations in the TCR gamma locus that we are currently exploring. Another output is a study we performed in response to the Covid-19 outbreak where we showed that specific BCR V gene variants are required to make a certain class of highly potent neutralizing SARS-CoV-2 antibodies. By combining personalized genotyping with the isolation of SARS-CoV-2 spike-specific monoclonal antibodies (mAbs), we showed that BCR V alleles that differ from each other by as little as a single amino acid yield antibodies with markedly different activities (Pushparaj et al. Immunity 2023). This work highlights the importance of understanding BCR V, D and J gene variation, and combining genetic and functional studies.

The most significant achievement in the ImmuneDiversity project has been to establish a highly precise, high throughput technique for typing human adaptive immune receptor genes, that is all BCR and TCR V, D and J genes. The ImmuneDiscover technique is based on a targeted multiple locus sequencing approach and computational analysis pipelines that ensure the specificity of the technique. The technique requires minimal amounts of genomic DNA and thus enables immune profiling from sources such as archived biobank DNA. This is a scientific breakthrough as it means that we can process not just hundreds, but thousands of samples in just a few months, which was technically unfeasible previously. During this ERC project, we applied ImmuneDiscover to over 2500 cases from the 1000 Genomes Project (1KGP) sample collection and other cohorts, comprising 5 super-populations (African, European, East Asian, South Asian and American), representing 25 sub-population groups. We have just completed the analyses of the BCR loci and identified over 500 novel IGHV alleles. We also determined the frequency of each allele in the 25 different groups, resulting in an atlas of gene variant present in the different populations, which we are reporting for the first time in an upcoming publication and a user-friendly website (Corcoran et al. manuscript in submission). This is a major undertaking, which we are currently extending to the TCR loci. Finally, we have used the ImmuneDiscover technique to sequence a large cohort of indviduals with rheumatoid arthritis and controls, generating an extensive data set that is now being analyzed.

We have presented our progress in several international conferences and workshops and we have initiated valuable pre-clinical and clinical collaborations where we utilize the ImmuneDiscover technique to study questions related to human evolution and autoimmune diseases.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Through our studies, we have shown that genetic diversity at the human TCR and BCR loci is extensive, both between individuals and populations. We have shown that a significant number of alleles that are found at high frequency in different populations are not represented in the current public reference databases. An even greater number of previously unreported alleles are found at a lower frequency, and many alleles are population specific. Through the work performed in this ERC grant, we have generated population-inclusive databases where the frequency of each allele in different populations is described. We have shown that the majority of V and J gene variations result in amino acid changes that can have functional implications, and we have reported examples demonstrating this. The papers describing the results from our population studies are now being written up for publication and we are analyzing the results from the first disease association studies. The IgDiscover and ImmuneDiscovery techniques developed in our group have proven to be extremely effective, generating results that are beyond the state-of-the-art, which will have great impact on the field of human immunology going forward. The adaptive immune system is important for many different aspects of human biology, including protection against pathogens, vaccine responses, cancer surveillance and autoimmunity. The results provided by our studies will provide a solid basis for identifying individual variation in BCR and TCR function and will inform future work in many aspects of human disease studies.

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