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Sestrins induce natural killer function in senescent-like CD8+ T cells


Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27CD28CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D–DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27CD28CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27CD28CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.

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Fig. 1: Transcriptional signature of human CD8+ T cell subsets.
Fig. 2: Single-cell RNA sequencing of TN and TEMRA CD8+ T cells.
Fig. 3: NK and senescence markers within TN and TEMRA cells.
Fig. 4: NKG2D–DAP12 complex mediates NK cytotoxicity in CD27CD28CD8+ T cells.
Fig. 5: Sestrins and Jnk MAPK dampen TCR signaling in CD27CD28CD8+ T cells.
Fig. 6: Sestrins regulate DAP12 and NKG2D expression in CD8+ T cells.
Fig. 7: Sestrins induce an age-dependent NK phenotype in CD8+ T cells in vivo.

Data availability

The data that support the findings of this study are available from the corresponding author upon request. The complete microarray data set is available online from the NCBI Gene Expression Omnibus public repository (GEO accession number GSE98640). The scRNA-seq data are available on EGA (accession number EGAS00001004255).


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We thank A. Toubert from INSERM U.1160 and Laboratoire d´Immunologie et d´Histocompatibilité, Hôpital Saint-Louis, Université Paris Diderot, Sorbonne Paris Cité for the kind gift of the C1RMICA cell line. B.I.P. was supported by the Portuguese Foundation for Science and Technology and the Gulbenkian Institute for Science sponsoring the Advanced Medical Program for Physicians (PFMA). This work was supported by the Medical Research Council (grant MR/P00184X/1 to A.N.A.), the Ministry of Education of Brazil (grant BEX9414/14-2 to L.P.C.), the Wellcome Trust (grant AZR00630 to A. Lanna), University College London Business (to S.M.H. and A.N.A. for the microarray work), the National Institutes of Health (R01DK102850 and R01DK111465 to J.H.L.), the NIH/NIAID (R01 AG052608 and R01 AI142086 to J.B.) and the Biotechnology and Biological Science Research Council (grant BB/L005336/1 to N.E.R.). R.P.H.D was supported, in part, by the NIHR UCL Hospital Biomedical Research Centre, and S.M.H. is funded by the Springboard award from the Academy of Medical Science and the Wellcome Trust. A.L. is a Sir Henry Wellcome Trust Fellow sponsored by M. L. Dustin (University of Oxford). S.M.J. is a Wellcome Trust Senior Fellow in Clinical Science and is supported by the Rosetrees Trust, the Welton Trust, the Garfield Weston Trust and the UCLH Charitable Foundation. S.M.J. and V.H.T. have been funded by the Roy Castle Lung Cancer Foundation. D.U. is supported by the National Institute of General Medical Sciences (NIGMS) under award number GM124922. G.A.K. is supported by the Travelers Chair in Geriatrics and Gerontology, as well as the National Institute on Aging (AG061456, AG048023, AG063528, AG060746, AG021600, AG052608 and AG051647).

Author information

Authors and Affiliations



B.I.P., L.P.C and R.P.H.D. designed and performed the experiments, analyzed the data and wrote the manuscript. D.N.-B. designed and analyzed the scRNA-seq data under the supervision of J.B. and D.U. R.M. performed all the experiments with the healthy older adult subjects. G.A.K. recruited all the healthy older adult donor subjects in Farmington, CT. A. Lanna, E.S.C. and N.E.R. designed and performed experiments. S.W. and J.S. designed and performed in vivo cytotoxicity studies. S.M.H. and A.N.A. designed and performed the microarray studies. A. Larbi provided support for studies of NKR on T cells. N.A.M., V.H.T. and S.M.J. analyzed the microarray and RNA-seq data. D.C.O.G., D.W.G., J.H.L. and M.K.M. facilitated mouse experiments. A.N.A. designed the experiments, reviewed and edited the manuscript, and organized the collaborative infrastructure.

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Correspondence to Arne N. Akbar.

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Peer review information Ioana Visan was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 CD8+ T cell gating and NKR expression.

a, Representative flow cytometry plots showing T cell gating and NKR expression on peripheral blood lymphocytes, specifically focusing on CD8+ T cell subsets stratified by the expression of CD27/CD45RA in healthy donors. Defined subsets are CD27+CD45RA+ TN, CD27+CD45RA TCM, CD27CD45RA TEM, and CD27CD45RA+ TEMRA cells. b, Confirmation of expression of CD57, KLRG1, CD244, NKG2D, NKG2C, and KIR2DL on TN (naive), TCM, TEM, and TEMRA CD8+ T cell subsets. Numbers in quadrants represent percentages of cells in each subset. Numbers above the histograms indicate the MFI. c, Flow cytometry gating of CD8+ T cells to confirm CD27 and CD28 expression in subpopulations based on CD27/CD45RA gating.

Extended Data Fig. 2 NKR expression in CD8+ and CD4+ T cells defined by CD27/CD28.

Expression of NK cell receptors (NKR) on a, CD8+ and b, CD4+ T cells assessed by flow cytometry on PBMCs from 22 healthy donors (median age = 52, range 25-83). Total CD8+ and CD4+ T cells were stratified into three subsets according to CD27/CD28 expression as shown in Extended Data Fig. 1a.

Extended Data Fig. 3 scRNA-seq method and quality control.

a, Overview of the scRNA-seq processing pipeline. Raw data (n=82,061 sorted CD8+ T cells) from six healthy older adult donors (six IL7R+ and six IL7R CD8+ T cell samples) were first cleaned from the multiplets, using Scrublet36, then merged, resulting in a data set containing 62,343 cells. After batch correction using BBKNN37, the Scanpy66 -based pipeline was ran (see Methods section). b, Number of cells per individual (n=12). IL7R+ (n=6, in green) and IL7R- (n=6; in purple). c, Number of genes per distribution across the IL7R+ (in green) and IL7R- (in purple) cells. d, Number of cells before (light orange) and after (light blue) filtration (that is, doublet removal and other filtration steps that are described in Methods), within each individual. e, Bar plot highlighting the cell abundances across clusters (n = 13) for 10X run batches (upper panel) and IL7R+ and IL7R groups (lower panel) after BBKNN batch effect correction. f, Bar plot highlighting the individual (n=12) cell abundances across clusters (n = 13) after BBKNN batch effect correction. Each color represents an individual. g, Number of cells in each cluster.

Extended Data Fig. 4 scRNA-seq comparison of re-clustered CD8+ T cells.

a, Violin plot showing the IL7R expression (as defined by scRNA-seq) across the 13 clusters. b, Dotplot showing the genes that are modulated in TN (top genes in red) and TEMRA (top genes in green) compartments. The scores (y axis) were defined using the Scanpy function (, based on Wilcoxon statistical test. FC = Fold change. TN (C0, C4 and C8) and TEMRA (C1, C2 and C6) compartments were extracted, a second round of clustering on the selected clusters (n = 39,634) was performed (as in Fig. 3) and UMAP plots highlighting c, IL7R groups (IL7R+ in green, IL7R in purple, as defined by flow sorting) and d, of representative genes are shown.

Extended Data Fig. 5 Extended data on cytotoxicity and Sesn2 expression.

a, Titration curve of varying effector to target (E:T) ratios on cytotoxicity measured as specific lysis of K562 cells using a calcein-release of CD27CD28CD8+ (DN) T cells and NK cells isolated by FACS. Non-linear regression (5-parameter asymmetric) was performed (means and s.d., n = 3 donors). b, Calcein-release cytotoxicity assay of K562 cells by CD27+CD28+ (DP), CD27+CD28 (SP), DN CD8+ T cells, and NK cells at E:T 20:1. Cytotoxicity was assessed over a period of six hours (means and s.d., n = 3 donors). c, Representative dot plot of MICA/B expression in C1R and C1R–MICA*008 cells. d, Representative histogram of NKG2D express ion on CD28CD8+ T cells after transfection with NK G2D siRNA (siNKG2D, black) or scrambled siRNA (siCtrl, gray), determined 36 hours after transfection. Numbers indicate MFI. e, Expression of DAP10 on human NK cells, and DP, SP, and DN CD8+ T cell subsets. Mean fluorescence intensity is shown (means and s.d., n = 4 for T cell, n = 3 NK cells). f, Sestrin 2 on CD8+ T cells from young (<35 years, n = 5) and old (>65 years, n = 4) donors. MFIs are shown (geometric means and geometric s.d. factor). Two-tailed, unpaired Welch’s t-test, ** p < 0.01.

Extended Data Fig. 6 YFV-tet+CD8+ T cells exhibit an NK phenotype.

Data mined from Akondy et al. (GSE100745)28 showing the relative fold change (log2) of differentially expressed genes of interest in YFV-tetramer+ effector (14 days post vaccination, black bars, n = 3) or memory (412 years post vaccination, red bars, n = 5) compared to naive (n = 6) CD8+ T cells.

Extended Data Fig. 7 Extended data on the murine delayed-type hypersensitivity model.

a, Spleen weight following mBSA-driven DTH response in young WT (Y WT, n = 4 mice), old WT (O WT, n = 8 mice), old Sesn1−/− (O Sesn1−/−, n = 5 mice), and old Sesn2−/− (O Sesn2−/−, n = 4 mice). Bars represent means and s.d.. b, Representative gating strategy to identify NK1.1+ NK cells (violet), TCRβ+CD1d tetramer reactive iNKT cells (purple), TCRβ+CD3+ CD4+ (blue) and CD8+ (red) T cells in mice. Similar results were obtained in all mice (n = 3 per group). c, Quantification of these cell types in the spleen (means and s.e.m., n = 3 mice per group). d, Dot plots showing relative frequencies of CD44CD62L+ naive (gray), CD44+CD62L+ central (blue), and CD44+CD62L effector (red) CD8+ T cells. e, Quantification of these cell types as a proportion of total splenic CD8+ T cells (means and s.e.m., n = 3 per group). f, Enumeration of NKG2D, NKG2A/C/E, KLRG1, Ly49, and NKp46 expression on CD8+ T cells from Y WT, O WT, O Sesn1−/−, and O Sesn2−/− mice (means and s.e.m., n = 3 per group). One-way ANOVA with Tukey’s multiple comparisons test. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

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Supplementary Table 1

Differentially expressed genes from microarray data.

Supplementary Tables 2–5

See tab “table legends” in file.

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Pereira, B.I., De Maeyer, R.P.H., Covre, L.P. et al. Sestrins induce natural killer function in senescent-like CD8+ T cells. Nat Immunol 21, 684–694 (2020).

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