Variation in immune cell receptor genes implicated in infection reactions

The genes that encode immune cell receptors differ substantially between people, giving scientists an insight into why people react differently to disease and medicine.

Researchers from the Karolinska Institutet, Sweden, publishing their findings in journal Immunity, used cutting-edge deep-sequencing technology to profile the differences in white blood cell T-cell receptors (TCRs), which play a role in immune response, in 45 humans from populations from different global regions. The scientists confirmed their findings by analysing several thousand further cases from the 1000 Genomes Project.

Professor Gunilla Karlsson Hedestam, the study lead, said, 'It was previously unknown how variable human TCR genes are,' and lead author of the paper, Dr Martin Corcoran, explained, 'We discovered 175 new gene variants, which doubles the number of known TCR gene variants. An unexpected and surprising finding is that certain gene variants originate from Neanderthals and one of these is present in up to 20 percent of modern humans in Europe and Asia.'

TCRs are proteins expressed on the surface of T-cells, a type of white blood cell responsible for recognising proteins expressed on abnormal cells, such as infections and cancer cells. T-cells trigger an immune response via TCRs, which display a high degree of diversity in order to recognise many infections and tumour cells.

Normal methods used in whole genome sequencing cannot identify the differences in the genes that encode TCRs. Therefore, the scientists used a deep sequencing technology called Rep-seq to define TCR genes to a high specificity.

Rep-Seq was able to read the variable regions of the genes that encode for TCRs, identify unique sequences within the cells and helped identify specific variants that are important for immune responses.

The researchers analysed the TCR genes from four human populations, African, East Asian, South Asian, and European, and showed that the genes had extensive diversity in both individuals and populations, identifying 175 new gene variants. The authors of the paper believe that this genetic diversity is due to a combination of naturally occurring mutations, natural selection, population bottlenecks, and genes passed down from ancestors.

'We found that every individual other than identical twins has a unique set of TCR gene variants. These differences reveal possible mechanisms underlying the wide range of responses to infections and vaccines that we observe at the population level', said Dr Corcoran.

Beyond demonstrating how variable the immune system is, these findings suggest an advantageous inheritance of TCR alleles from ancient populations. The group is now interested in understanding how immune system genetics could lead to advances in therapeutics, such as immunotherapy, where genetically modified T-cells are already used with promising success in CAR-T gene therapy (see BioNews 1172, 1165 and 1131).