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.
