An international team of scientists at the University of New Mexico, Monash University, and the NIH has defined a novel T cell lineage, called γμ T cells, found only in marsupials (e.g., kangaroos and opossums) and monotremes (e.g., duckbill platypus). Evidence for the γμ TCR came with the discovery of genes encoding the TCRμ protein while analyzing the first complete marsupial genome, that of the South American opossum Monodelphis domestica. Distinct from conventional αβ and γδ TCRs, TCRμ was predicted to share similarity with the antibodies.

The researches published their study “The molecular assembly of the marsupial γμ T cell receptor defines a third T cell lineage” in Science.

“αβ and γδ T cell receptors (TCRs) are highly diverse antigen receptors that define two evolutionarily conserved T cell lineages. We describe a population of γμTCRs found exclusively in non-eutherian mammals that consist of a two-domain (Vγ-Cγ) γ-chain paired to a three-domain (Vμ-Vμj-Cμ) μ-chain. γμTCRs were characterized by restricted diversity in the Vγ and Vμj domains and a highly diverse unpaired Vμ domain,” write the investigators.

“Crystal structures of two distinct γμTCRs revealed the structural basis of the association of the γμTCR heterodimer. The Vμ domain shared the characteristics of a single-domain antibody within which the hypervariable CDR3μ loop suggests a major antigen recognition determinant. We define here the molecular basis underpinning the assembly of a third TCR lineage, the γμTCR.”

Using the Australian Synchrotron, the scientists at Monash University obtained a detailed three-dimensional image of the opossum γμTCR architecture that was unique and distinct from αβ or γδ TCRs. Noteworthy was the presence of an additional single antibody-like segment called Vμ domain with an architecture resembling to nanobodies, a unique type of antibodies. This discovery raises the possibility that γμ T cells recognize pathogens using novel mechanisms, distinct from conventional T cells.

“The discovery of a nanobody like structure in the γμ TCR has the potential to expand the immunology ‘toolbox.’ Indeed, nanobodies discovered in the camel family (e.g. alpacas) have recently attracted considerable interests for their development as research and diagnostic tools and more importantly as immunotherapeutics in humans to combat cancer and viral infections such as COVID-19. Marsupials may offer an alternative source of nanobodies, one that is smaller, easier and cheaper to maintain than llamas or alpacas.” said Monash University’s Marcin Wegrecki, PhD, from the Biomedicine Discovery Institute, co-first author on the paper.

“Our findings further illustrate the value of exploring the world’s biodiversity for novelty beyond the standard animal research models, such as laboratory mice. Modern genomic tools applied to many species have opened the door to the myriad of immunological solutions to fighting pathogens that evolution has produced.” added Robert Miller, PhD, from the University of New Mexico, co-lead author on the paper.

“Many in-roads have been made in understanding the immune systems of humans and mice leading to the development of novel immunotherapeutic approaches enabling humans to combat highly pathogenic viruses. However, much less is understood on how immunity operates in other species that, in some cases, have been decimated by wildlife diseases. Ultimately our work may guide the development of veterinary approaches (e.g. novel vaccines) that will contribute to wildlife conservation.” noted Jérôme Le Nours, PhD, from Monash Biomedicine Discovery Institute, co-lead author on the paper. “This is a prime example of curiosity driven science leading to unexpected and transformative findings.”