#PLOSBiology: Single-cell transcriptomics of the naked mole-rat reveals unexpected features of mammalian ... dx.plos.org/10.1371/journa…
Our article describing the immune system of the long-lived and cancer-resistant naked mole-rat published @PLOSBiology today. A brief(ish) thread 👇
Our article describing the immune system of the long-lived and cancer-resistant naked mole-rat published @PLOSBiology today. A brief(ish) thread 👇
The naked mole-rat is long-lived (~30y!) and doesn't seem to get cancer very often. But almost nothing is known about its immune system. In this study we used single-cell RNA sequencing of the blood and spleen to remedy that. Needless to say, we found some weird stuff....
The naked mole-rat has half the number of lymphoid cells found in the laboratory mouse (44% vs 90%). The major difference here comes from B-cells (14% vs 59%). The naked mole-rat makes up for this with more granulocytes and APCs.
Some of the naked mole-rat cell subsets have unusual gene expression. Perhaps the best example we found was that at least some of their dendritic cells have very high expression of the Timeless gene.
The naked mole-rat lacks cell populations found in the mouse and vice-versa: we found a population of neutrophil-like cells in the mole-rat that have very high expression of the Ltf gene (distinct from the rest of their neutrophils). No sign of these in the mouse.
Most surprising (especially for this NK cell biologist) - we didn't find any NK cells in the mole-rat. Our first thought was this was a technical bias introduced by the scRNAseq workflow/analysis and so we tried really hard to find them... (see paper for details)
The mole-rat DOES have a population of cells with high expression of Gzma and Nkg7 (so why don't we think these are NK cells?) - because they are also the only subset of cells that express high levels of Cd3 and Cd8a (more consistent with them being CD8 T-cells)
Wouldn't it be odd if the mole-rat genome contained a bunch of genes that control NK cell function if they didn't have NK cells? We thought so, so we went looking for some. Other rodents (mice, rats) have lots of Ly49 genes that recognize MHC-I and control NK cells...
But mole-rats have virtually none. Also no diverse Ig-like NK receptors like primates. They also have very few MHC-I genes. This lack of diversity isn't unprecedented (some marine carnivores roll this way too) but it's very different from most mammals (we checked 45 genomes)
Finally, we wanted to know how the mole-rat responded to immune stimulation, so we compared mouse and mole-rat responses to LPS. Both species engage broadly similar responses, centered around the NFKB pathway. But those Ltf-high neutrophils we found light up like a Xmas tree...
Take home message: mole-rat immune systems have some novel features not found in other mammals. More work needed to assess immune function and confirm provocative findings of this study, particularly wrt NK cells and whether immune system impacts longevity and cancer resistance
Open questions - which came first, no NK cells or no cancer? Are mole-rats susceptible to viral infection if they really have no NK cells? Do other mammals with limited NKC/LRC diversity also lack NK cells? What mechanisms have evolved to compensate for no NK cells?
