High diversity in T-cell receptor genes explains diverse response to infections

Researchers from Karolinska Institutet have demonstrated that the genes that encode the T cell receptors change significantly between individuals and communities, which could help explain why people react differently to certain diseases. The research, which was published in the journal Immunity, also shows that Neanderthals passed along some gene variants.

The immune system’s T-cells are essential for defending against cancer and infections. The cells identify cancerous cells and foreign intruders with the aid of TCRs.

It was previously unknown how variable human TCR genes are.”

Gunilla Karlsson Hedestam, Study Lead Author and Professor, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet

Persons from different parts of the world were included

The researchers studied the TCR genes in 45 individuals from sub-Saharan Africa, East Asia, South Asia, and Europe using deep sequencing of blood samples.

The study demonstrated that these genes vary substantially between various people and population groupings. Analyses of several thousand additional instances from the 1000 Genomes study served as confirmation for the findings.

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.”

Martin Corcoran, Study First Author and Senior Research Specialist, Karolinska Institutet

He added, “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% of modern humans in Europe and Asia.”

According to Gunilla Karlsson Hedestam, the development of specialized deep sequencing methods and analysis software that permits the extremely precise definition of B- and T-cell receptor genes has made it possible to detect the variation in these genes. Previously, this was not possible with the standard methods used in whole genome sequencing.

Corcoran further added, “As these genes are among the most variable in our genome, the results also provide new information about how our immune system has developed over the course of history, says Martin Corcoran. We are particularly interested in uncovering the function of the TCR variants we have inherited from Neanderthal ancestors. The frequency of these variants in modern humans suggests an advantageous function in our biology and we are keen to understand this.”

Can lead to new treatments

Future development of novel treatment strategies could benefit immensely from the discoveries and the new TCR gene database that the researchers are currently publishing.

“Understanding human genetics is fundamental for the development of targeted treatments. The methods described in the study provide new opportunities, not the least in the cancer field where T-cells are central to several promising forms of immunotherapy,” Hedestam added.

The findings could also offer insight into different fields of study.

Hedestam further stated, “The findings can lead to the development of new diagnostics and therapies in a range of medical disciplines, including precision medicine.”

Talking about the next step in their research, Hedestam added, “We are now investigating the functional significance of several of the newly discovered gene variants and how this variation impacts our T-cell responses. We are also planning extended studies involving large groups of individuals to examine the role of TCR gene variation in diseases we know involve T cells, such as infectious diseases, cancer, and autoimmune disorders.”