Abstract
The immune system comprises a complex network of specialized cells that protects against infection, eliminates cancerous cells, and regulates tissue repair, thus serving a critical role in homeostasis, health span, and life span. The subterranean-dwelling naked mole-rat (NM-R; Heterocephalus glaber) exhibits prolonged life span relative to its body size, is unusually cancer resistant, and manifests few physiological or molecular changes with advancing age. We therefore hypothesized that the immune system of NM-Rs evolved unique features that confer enhanced cancer immunosurveillance and prevent the age-associated decline in homeostasis. Using single-cell RNA-sequencing (scRNA-seq) we mapped the immune system of the NM-R and compared it to that of the short-lived, cancer-prone mouse. In contrast to the mouse, we find that the NM-R immune system is characterized by a high myeloid-to-lymphoid cell ratio that includes a novel, lipopolysaccharide (LPS)-responsive, granulocyte cell subset. Surprisingly, we also find that NM-Rs lack canonical natural killer (NK) cells. Our comparative genomics analyses support this finding, showing that the NM-R genome lacks an expanded gene family that controls NK cell function in several other species. Furthermore, we reconstructed the evolutionary history that likely led to this genomic state. The NM-R thus challenges our current understanding of mammalian immunity, favoring an atypical, myeloid-biased mode of innate immunosurveillance, which may contribute to its remarkable health span.
Highlights
In order to obtain cell repertoires of the naked mole-rat (NM-R) and mouse immune systems, spleens were harvested from young healthy C57BL/6 mice (2–3 months old; n = 4) and NM-Rs and a 10× Genomics [7] droplet-based scRNA-seq library was prepared from each organ (S1A–S1D and S1H–S1K Fig)
We find that the immune system of the NM-R is heavily reliant on innate myeloid lineage cells, lacks natural killer (NK) cells, and contains a previously undescribed, transcriptionally distinctive cell subset that is highly responsive to a bacterial-mimicking challenge
To the best of our knowledge, our study is the first to report a mammalian species that lacks a clearly defined population of NK cells that form the first line of defense against viral infections and play an important role in cancer immunosurveillance [23]
Summary
The immune systems of the NM-R and mouse have strikingly different cellular compositions. To confirm the interspecies differences we observed in our scRNA-seq data, we used comparative histomorphology and in situ hybridization (ISH; Materials and methods) This revealed major interspecies differences in the distribution of the red and white pulp (S2A Fig), with significantly higher expression of Cd19 (B cell marker) and lower expression of Cd14 (myeloid lineage marker) in the mouse than in the NM-R (S2B–S2D Fig; S5 Table). Our analysis included the detection of old and unannotated NK cell receptor and MHC-I pseudogenes in order to reconstruct their evolutionary histories (Materials and methods; S7 Fig, S12 and S13 Tables) This revealed that the Ly49 gene family expanded from the single ancestral gene to three members prior to the Lagormorpha-Rodentia split (Fig 2D). Spleen scRNA-seq revealed that cells from both saline control and LPS-challenged animals of both species clustered into similar cell types to those observed in untreated animals (Fig 3A and 3B; S18–S25 Tables). These results strongly suggest that NM-Rs have two transcriptionally distinct but functionally integrated neutrophil populations that likely play an important role in innate antimicrobial immunity in this species
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