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Series GSE214390 Query DataSets for GSE214390
Status Public on Nov 30, 2023
Title The evolution of the naked mole-rat T cells
Organisms Mus musculus; Heterocephalus glaber
Experiment type Expression profiling by high throughput sequencing
Summary The immune system consists of a network of specialized cells and processes that protect the organism from diseases and regulates tissue repair. Natural killer (NK) cells and the αβ and γδ T cells comprise the cytotoxic arm of the immune system and have evolved to detect and eradicate cells infected with pathogens and affected by malignancies, in order to prevent their spread and subsequent tissue damage. The naked mole-rat (NMR; Heterocephalus glaber) exhibits an unusually long lifespan relative to its body size, remarkable cancer resistance, and a surprising absence of NK cells, likely lost during its evolution. So far, little is known about NMR T cells in terms of the subsets they comprise, the evolution of the genes that regulate their function, the diversity of their clonotypes, and the organ in which they mature – the thymus. Using single-cell RNA sequencing (scRNA-seq), we find that NMRs have a large population of circulating γδT cells, comprising two subsets, one with an activated cytotoxic profile. Using comparative genomics, we find that the NMR genome maintains a large diversity of γ and δ variable T-cell receptor (TCR) regions, relative to that in other mammalian genomes. We devise a novel TCR scRNA-seq approach, which reveals that the NMR cytotoxic γδT-cell subset harbors a dominant clonotype, and that, in contrast to mouse, the clonotypic diversity of NMR CD8 αβT cells is significantly lower than that of its CD4 αβT cells. The latter suggests that NMRs have evolved under a relaxed intracellular pathogenic selective pressure, consistent with the loss of their NK cells. We corroborate this by showing that the genomic diversity of NMR MHC-I genes, relative to that of MHC-II genes, is considerably smaller than in other mammalian genomes. In line with these findings, we further show that NMR thymi in early life are considerably smaller compared to mouse thymi, yet by middle age thymi of both species show equivalent signs of involution. Our study thus sheds significant light on NMR T cells and moves us one step closer towards understanding the contributions of the immune system to the remarkable longevity and cancer resistance of this species.
 
Overall design Single-cell short-read RNA-seq 10X samples of adult and old naked mole-rat and mouse anti-CD3 sorted splenocytes (hence T cells), adult naked mole-rat and mouse bone-marrow cells, adult naked mole-rat and mouse thymocytes; Single-cell long-read RNA-seq PacBio samples of adult and old naked mole-rat and mouse anti-CD3 sorted splenocytes (hence T cells)
 
Contributor(s) Lin TD, Rubinstein ND, Fong NL, Smith M, Craft W, Martin-McNulty B, Roy MA, Buffenstein R
Citation(s) 38605005
Submission date Sep 28, 2022
Last update date May 01, 2024
Contact name Nimrod Daniel Rubinstein
E-mail(s) nrubinstein@calicolabs.com
Phone 9193082834
Organization name Calico
Street address 1170 Veterans blvd
City South San Francisco
State/province CA
ZIP/Postal code 94080
Country USA
 
Platforms (4)
GPL19057 Illumina NextSeq 500 (Mus musculus)
GPL24046 Illumina NextSeq 500 (Heterocephalus glaber)
GPL29177 Sequel II (Mus musculus)
Samples (66)
GSM6605086 adult naked mole-rat anti-CD3 sorted splenocyte short-read 10x scRNA-seq, replicate 1
GSM6605087 adult naked mole-rat anti-CD3 sorted splenocyte short-read 10x scRNA-seq, replicate 2
GSM6605088 adult naked mole-rat anti-CD3 sorted splenocyte short-read 10x scRNA-seq, replicate 3
Relations
BioProject PRJNA885113
SRA SRP400081

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE214390_RAW.tar 3.9 Gb (http)(custom) TAR (of MTX, TSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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