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Mapping the naked mole-rat immune system

Naked mole-rats are animals with unusually long lifespans, especially when compared with other animals of similar size. The Buffenstein lab at Calico has shown that these mouse-size rodents show attenuated aging profiles, well-maintained good health and rarely get cancer or other age-related diseases. Rochelle (Shelley) Buffenstein, a Senior Principal Investigator at Calico, asked if there was something unique about the naked mole-rats’ immune system that confers these health advantages.

A joint effort between the Buffenstein lab, our genomics technology group, and computational scientists at Calico, as well as a pathologist at UC Davis, revealed new and important insights about the naked mole-rat immune system.

The team used single-cell RNA sequencing to compare the spleen cells of the naked mole-rat to that of the well-characterized lab mouse. Striking differences in the immune cell distribution between species were observed using both transcriptomic and immunohistochemical approaches -- naked mole-rats appear to have a novel innate myeloid immune cell type, but most surprisingly lack natural killer (NK) cells, an immune cell type known to be important in dealing with both viruses and cancers.

The absence of NK cells was most unexpected because in both humans and mice, NK cells are thought to be crucial for eliminating cancer cells in the body. So why does a species that rarely gets cancer not have this important immune cell type?

The answer proved to be more complicated and required “quite a bit of evolutionary genetics computational work to nail down,” said Nimrod Rubinstein, an evolutionary geneticist by training and a Principal Data Scientist at Calico, who was the computational lead of this study and a lead author on the paper. His computational detective work suggested that naked mole-rats most likely had lost these NK cells during the course of their evolution, probably because there was no strong natural selective pressure for their maintenance. In support of this premise, Nimrod found that many of the genes that regulate NK cell function were dysfunctional in the naked mole-rat. Rather, they are present in the genome as inactive pseudogenes, suggesting that while they may once, millions of years ago, have been functional. They remain in the genome as relics of their past -- they are “dead genes.”

Shelley suggested that a possible explanation may be linked to the reduced burden of viral infections in the sealed underground burrows that naked mole-rats have inhabited for millions of years. Here, they are isolated from airborne contagious agents, other species and unrelated conspecifics that may carry potential viral burdens.

NK cells are critical for the elimination of virally-infected cells that may kill the individual and even lead to species extinction if an infection goes unchecked. In contrast, cancers typically occur late in life after sexual maturity and the propagation of offspring.

Protection against cancer is not subject to natural selection to the same extent and it is likely that the naked mole-rat’s reduced evolutionary burden of viral infections possibly contributed to the loss of NK cells, adds Nimrod.

Nimrod is excited about these findings because they are key for better understanding the health-related secrets of the naked mole-rat by providing a ‘manual’ of their immune system with fascinating chapters describing how it evolved. Immune studies are ongoing, with TzuHua (Dennis) Lin in the Buffenstein lab leading investigations into whether or not other cells have usurped the role of NK cells and the role of the novel myeloid population in inflammation resolution.

Read the paper in PLOS here.

Read more about how naked mole-rats don’t age. 
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