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Distinct organization of adaptive immunity in the long-lived rodent Spalax galili

Nature Aging volume 1, pages 179–189 (2021)Cite this article

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Abstract

A balanced immune response is a cornerstone of healthy aging. Here, we uncover distinctive features of the long-lived blind mole-rat (Spalax spp.) adaptive immune system, relative to humans and mice. The T-cell repertoire remains diverse throughout the Spalax lifespan, suggesting a paucity of large long-lived clones of effector-memory T cells. Expression of master transcription factors of T-cell differentiation, as well as checkpoint and cytotoxicity genes, remains low as Spalax ages. The thymus shrinks as in mice and humans, while interleukin-7 and interleukin-7 receptor expression remains high, potentially reflecting the sustained homeostasis of naive T cells. With aging, immunoglobulin hypermutation level does not increase and the immunoglobulin-M repertoire remains diverse, suggesting shorter B-cell memory and sustained homeostasis of innate-like B cells. The Spalax adaptive immune system thus appears biased towards sustained functional and receptor diversity over specialized, long-lived effector-memory clones—a unique organizational strategy that potentially underlies this animal’s extraordinary longevity and healthy aging.

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Fig. 1: Comparative phylogenetic analysis of Spalax, mouse and rat TCR and IGH genes.
Fig. 2: TCR diversity and thymus involution.
Fig. 3: Characteristics of TCR CDR3β repertoires for four age groups in Spalax, mouse and human.
Fig. 4: Expression of T-cell-related genes in mouse and Spalax spleen across age groups.
Fig. 5: Immunoglobulin repertoire features in Spalax and mouse across age groups.

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Data availability

TCR and IGH profiling and RNA-seq raw sequencing data were deposited in GenBank under BioProjects PRJNA432350 and PRJNA643223. Spalax TCR and IGH gene references are available at https://doi.org/10.5281/zenodo.4473340. Extracted TCR clonesets, gene expression data and cloneset metrics are available in figshare: https://figshare.com/projects/Distinct_organization_of_adaptive_immunity_in_long-lived_rodent_Spalax_Galili/28773.

Code availability

See Supplementary Note 2 for the de novo transcriptome assembly pipeline. MiXCR software is available from MiLaboratory LLC: https://milaboratory.com/.

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Acknowledgements

We thank O. Schwartz and E. Suss-Toby, BCF Bioimaging Center, Faculty of Medicine, Technion, for the MR imaging and image analysis. The work was supported by the Russian Science Foundation (grant no. 16-15-00149, to O.V.B.), the Ministry of Education and Science of the Russian Federation (grant no. 14.W03.31.0005, to D.M.C., for part of mouse samples preparation) and the Israel Science Foundation (grant no. 1935/17, to I.S.). M.M. was supported by the European Regional Development Fund–Project ‘MSCAfellow3@MUNI’ (grant no. CZ.02.2.69/0.0/0.0/19_074/0012727).

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Author notes

  1. These authors contributed equally: M. Izraelson, M. Metsger, A.N. Davydov.

  2. These authors jointly supervised this work: I. Shams, O. V. Britanova, D. M. Chudakov.

Authors and Affiliations

  1. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia

    M. Izraelson, I. A. Shagina, A. S. Obraztsova, I. Z. Mamedov, T. O. Nakonechnaya, M. Shugay, D. A. Bolotin, D. B. Staroverov, G. V. Sharonov, S. Lukyanov, O. V. Britanova & D. M. Chudakov

  2. Privolzhsky Research Medical University, Nizhny Novgorod, Russia

    M. Izraelson, I. Z. Mamedov, L. N. Volchkova, T. O. Nakonechnaya, M. Shugay, D. B. Staroverov, G. V. Sharonov, E. V. Zagaynova & D. M. Chudakov

  3. Pirogov Russian National Research Medical University, Moscow, Russia

    M. Izraelson, I. A. Shagina, I. Z. Mamedov, T. O. Nakonechnaya, M. Shugay, D. A. Bolotin, D. B. Staroverov, G. V. Sharonov, S. Lukyanov & D. M. Chudakov

  4. Central European Institute of Technology, Brno, Czech Republic

    M. Metsger, A. N. Davydov, I. Z. Mamedov & D. M. Chudakov

  5. Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel

    M. A. Dronina, D. A. Miskevich & I. Shams

  6. Institute of Systematics and Ecology of Animals SB RAS, Novosibirsk, Russia

    E. Y. Kondratyuk

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  1. M. Izraelson
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Contributions

M.I., I.A.S., M.A.D., D.A.M., I.Z.M., L.N.V., T.O.N., D.B.S., G.V.S., E.Y.K., I.S. and O.V.B. performed wet laboratory experiments. M.I., M.M., A.N.D., A.S.O., M.S., D.A.B. and O.V.B. performed data analysis. E.V.Z., S.L., I.S., O.V.B. and D.M.C. designed and supervised the project, designed experiments and worked on the manuscript. I.S., O.V.B. and D.M.C. are the co-senior authors.

Corresponding authors

Correspondence to O. V. Britanova or D. M. Chudakov.

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The authors declare no competing interests.

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Peer review information Nature Aging thanks Vera Gorbunova and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Phylogenetic tree of nucleotide sequences of IGVH segments.

The gene segments are highlighted in blue for mouse, orange for Spalax, and green for rat. Number after asterisk corresponds to the allele name. Only functional alleles are shown. The neighbour-joining trees were constructed with the evolutionary distances computed using the Maximum Composite Likelihood method, with a bootstrap of 1,000 replicates.

Extended Data Fig. 2 Phylogenetic tree of nucleotide sequences of TRAV segments.

Gene segments are highlighted in blue for mouse, orange for Spalax, and green for rat. The neighbour-joining trees were constructed with the evolutionary distances computed using the Maximum Composite Likelihood method, with a bootstrap of 1,000 replicates. The tree is drawn to scale, with branch lengths in the same units as the evolutionary distances used to output the phylogenetic tree. Number after asterisk corresponds to the allele name. Only functional alleles are shown.

Extended Data Fig. 3 Assessing the size of the thymus in young and adult Spalax.

a. Histological verification of thymic tissue localization showing its connection to surrounding tissues. Paraffin-embedded tissue after PFA fixation. Hematoxylin and eosin staining of section from young Spalax (<3 years) at 20x magnification. H - heart (aorta), T - thymus. Staining was performed on two animals. a,b. Representative thymus MRI sequential images for young (b) and old (c) Spalax showing the sagittal sections. White arrows point to the thymic lobes.

Extended Data Fig. 4 Physicochemical characteristics of TCR CDR3β repertoires.

Mean characteristics of the five amino acid residues in the center of CDR3β are shown for the four age groups in human, mouse, and Spalax. The measured parameters are a, normalized strength (strongly interacting amino acids), b, normalized volume (bulky amino acids), and c, normalized hydrophobicity (based on inverted Kidera factor 4). P-values were calculated using two-sided Welch’s t-test. * < 0.05, ** < 0.01, *** - < 0.001, ****<0.0001. n = 19 mice and 17 Spalax animals.

Extended Data Fig. 5 Expression of T-cell-related genes in mouse and Spalax spleen across age groups.

Expression of a, T cell transcription factors, b, checkpoint molecules, and c, naive/homeostatic genes, presented as non-normalized TPM values (corresponding to data shown in Fig. 4b–d). a-c. P-values represent one-way ANOVA with Tukey’s test, * < 0.05, ** < 0.01, *** - < 0.001. The boxplots visualize the median, hinges representing the 25th and 75th percentiles, and whiskers extending to the values that are no further than 1.5 × IQR from the upper or the lower hinge. n = 12 mice and 12 Spalax (3 animals per age group) were used for the analysis. d,e. Expression levels of (d) basic cytokines and (e) receptors (non z-scaled data corresponding to data shown in Fig. 4e,f). The P-value and Log-transformed fold changes (Log2FC) shown on the left represent the differential gene expression analysis results calculated between species (9 animals for each species excluding newborn, 3 animals per age group) according to the procedure described in the Methods section.

Extended Data Fig. 6 Busco analysis of transcriptome completeness.

Cumulative percentage of orthologues calculated using BUSCO with --auto-lineage-euk option against four transcriptome assemblies prepared by different tools (Shannon, SPAdes with kmer size of 55 and 75, Trinity). The Final_assembly represents the result of EvidentialGene pipeline applied to the merged data from 4 different assemblies.

Supplementary information

Supplementary Information

Supplementary Notes 1 and 2 and Tables 1, 3 and 4.

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Izraelson, M., Metsger, M., Davydov, A.N. et al. Distinct organization of adaptive immunity in the long-lived rodent Spalax galili. Nat Aging 1, 179–189 (2021). https://doi.org/10.1038/s43587-021-00029-3

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