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Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer

Nature Immunology (2025)Cite this article

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Abstract

CD8+ T cells are major mediators of antiviral and antitumor immunity. During persistent antigen stimulation as in chronic infection and cancer, however, they differentiate into exhausted T cells that display impaired functionality. Precursors of exhausted T (TPEX) cells exhibit stem-like properties, including high proliferative, self-renewal and developmental potential, and are responsible for long-term CD8+ T cell responses against persistent antigens. Here we identify the chromatin organizer and transcriptional regulator SATB1 as a major regulator of exhausted CD8+ T cell differentiation. SATB1 was specifically expressed in TPEX cells where it limited population expansion and effector differentiation while preserving functionality of CD8+ T cells. SATB1 downregulation was required for TPEX cell-to-effector cell differentiation in chronic infection and contributed to coordinated effector and memory differentiation in acute viral infection. DNA binding of SATB1 regulated gene expression both dependent and independent of chromatin accessibility. Finally, SATB1 limited antitumor CD8+ and chimeric antigen receptor T cell immunity. Overall, our results identify SATB1 as a central regulator of precursor fate and effector differentiation of CD8+ T cells both in infection and in cancer.

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Fig. 1: SATB1 limits population expansion of exhausted CD8+ T cells.
Fig. 2: SATB1 maintains functionality of CD8+ T cells in chronic infection.
Fig. 3: SATB1 limits proliferation of chronically stimulated CD8+ T cells.
Fig. 4: SATB1 downregulation is required for effector differentiation in chronic infection.
Fig. 5: SATB1 maintains polyfunctionality in acute viral infection.
Fig. 6: SATB1 regulates gene expression independent of chromatin accessibility.
Fig. 7: SATB1 limits tumor control and response to checkpoint inhibition.
Fig. 8: SATB1 is expressed in human TPEX cells and restricts CD8+ CAR T cell expansion and effector differentiation in vivo.

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Data availability

The ATAC-seq and RNA-seq data are available under accession numbers GSE281275 and GSE281382.

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Acknowledgements

This study was supported by a National Health and Medical Research Council (NHMRC) Investigator Grant (2017420 to A.K.), NHMRC Ideas and Project Grants (1147409 to A.K., 2028921 to L.R. and C.T., 1185346 to A.K. and 1003131 to S.J.T.), an Australian Research Council grant (DE240100827 to C.T.), a Cancer Council grant (to A.K.), the Melbourne Research Scholarship (L.H., S.K.M.W., S.L., M.H.S., C.G.G. and N.T.H.-A.), the Deutsche Forschungsgemeinschaft (DFG) via a Postdoctoral Fellowship (L.R.), IRTG2168 272482170 (Z.A., H.H. and M.D.B.), DFG EXC2151 (390873048 to Z.A. and M.D.B.), CRC237/B15/B17 (369799452 to Z.A.), CRC1454 (432325352) (to Z.A. and M.D.B) and a CSL Centenary Fellowship (D.T.U.). Furthermore, M.D.B. is supported by the EU-funded project NEUROCOV, the RIA HORIZON Research and Innovation under GA 101057775 and the Else–Kröner–Fresenius Foundation (2018_A158). We thank the NIH Tetramer Facility for providing us with tetramers. We thank the Melbourne Cytometry Platform for providing flow cytometry services and the Doherty Institute Biological Resource Facility for animal husbandry and management.

Author information

Author notes

  1. These authors contributed equally: Lisa Rausch, Michael H. Shannon.

Authors and Affiliations

  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

    Leonie Heyden, Lisa Rausch, Michael H. Shannon, Lachlan Dryburgh, Marcela L. Moreira, Aleksej Frolov, Sharanya K. M. Wijesinghe, Sining Li, Nhat Truong Huynh-Anh, Catarina Gago da Graça, Carlson Tsui, Bianca von Scheidt, Simone L. Park, Laura K. Mackay, Daniel T. Utzschneider, Jan Schröder & Axel Kallies

  2. Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany

    Leonie Heyden, Helena Horvatic, Zeinab Abdullah & Axel Kallies

  3. Immunogenomics and Neurodegeneration, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany

    Aleksej Frolov, Maren Köhne & Marc D. Beyer

  4. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Christina M. Scheffler, Marit J. van Elsas, Junming Tong, Olivia Hidajat & Phillip K. Darcy

  5. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia

    Christina M. Scheffler, Marit J. van Elsas, Junming Tong, Olivia Hidajat & Phillip K. Darcy

  6. Genomics and Immunoregulation, LIMES Institute, University of Bonn, Bonn, Germany

    Daniel Sommer

  7. Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany

    F. Thomas Wunderlich

  8. Department of Microbiology, The Biomedical Discovery Institute, Monash University, Melbourne, Victoria, Australia

    Stephen J. Turner

  9. Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany

    Marc D. Beyer

  10. PRECISE Platform for Single Cell Genomics and Epigenomics, DZNE, University of Bonn, and West German Genome Center, Bonn, Germany (DZNE), Bonn, Germany

    Marc D. Beyer

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  1. Leonie Heyden
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  2. Lisa Rausch
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Contributions

L.H. and A.K. conceived the study, designed the experiments, interpreted the results and wrote the paper. L.H. performed the majority of the experiments with help from M.H.S., S.K.M.W., S.L., N.T.H.-A., C.G.G. and H.H. L.R. performed and analyzed the tumor experiments. Z.A., S.J.T., M.D.B. and D.T.U. contributed to conceptualization and supervision of the study. L.D., A.F., J.S. and M.D.B. performed bioinformatic analyses. M.L.M. and L.H. performed the bulk RNA-seq and ATAC-seq experiments. C.T. performed the scRNA-seq experiment. M.D.B., M.K., D.S. and F.T.W. created the Satb1 transgenic and flexed mouse models. C.M.S., M.J.E., J.T., O.H. and P.K.D. performed the CAR T cell experiments. S.L.P., B.v.S. and L.K.M. created the B16-GP33 tumor cell line. S.J.T. provided key reagents.

Corresponding author

Correspondence to Axel Kallies.

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Competing interests

A.K. receives research support from Pfizer. The other authors declare no competing interests.

Peer review

Peer review information

Nature Immunology thanks Hazem Ghoneim, Charalampos Spilianakis and Tuoqi Wu for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editor: Laurie A. Dempsey, in collaboration with the Nature Immunology team.

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Extended data

Extended Data Fig. 1 SATB1 limits TEX cell differentiation.

(a) Histogram and quantification showing the expression of SATB1 in polyclonal PD-1+ TPEX and TEX cells compared to naïve CD8 T cells and B cells (n = 10). (b-e) Naïve SATB1-deficient mice (Satb1flex/flex/Cd8Cre, SATB1-KO) or control mice (Satb1flex/flex) were analyzed using flow cytometry. (b) Flow cytometry plots displaying GFP expression upon Cre-mediated Satb1 gene flip in CD8+ T cells of KO mice compared to control mice (n = 5). (c) Quantification of SATB1 expression in CD4+ and CD8+ T cells (n = 5). (d) Numbers of splenic CD4+ and CD8+ T cells in SATB1-KO and control mice (n = 5). (e) Flow cytometry plots and quantification showing CD44 vs CD62L expression in SATB1-KO and control mice and quantification of naïve and memory phenotype CD8+ T cells (n = 5). (f-i) Naïve CD45.2+ SATB1-KO P14 cells or control cells P14 cells were adoptively transferred into naïve wildtype CD45.1+ mice and subsequently infected with LCMV-Docile. On day 12, 21, and 28 p.i. spleens were analyzed using flow cytometry. (f) Flow cytometry plots showing frequencies and numbers of SATB1-KO or control TPEX and TEX cells. (g) Flow cytometry plots and quantification on days 12 (upper) (n = 8) and 21 (lower) (n = 14) p.i. showing frequencies and numbers of SATB1-KO or control CD62L+ TPEX cells. (h) Flow cytometry plots and quantification on day 28 p.i showing the frequencies and numbers of SATB1-KO or control P14 cells (n = 5). (i) Flow cytometry plots and quantification on day 28 p.i showing the numbers of SATB1-KO and control TPEX, total TEX, CX3CR1+ TEX and CD101+ TEX cells (n = 5). Flow cytometry plots are representative. Dots in graphs represent individual mice; horizontal lines and error bars of bar graphs indicate means ± SEM, respectively. Data are pooled (a,f,g) or representative (b-e, h,i) from two (day 12, day 28 p.i.) or three (day 21 p.i.) independent experiments. P values are from two-tailed unpaired student’s t test.

Extended Data Fig. 2 SATB1 promotes functionality of exhausted T cells.

(a-h) Naïve CD45.2+ SATB1-deficient P14 cells (Satb1flex/flex/Cd8Cre, SATB1-KO) or control cells (Satb1flex/flex) P14 cells were adoptively transferred into naïve wildtype CD45.1+ mice and subsequently infected with LCMV-Docile. On days 12 and 21 p.i. spleens were analyzed using flow cytometry. (a) Flow cytometry plots and quantification of SATB1-KO or control P14 cells producing IFN-γ and TNF and quantification of IFN-γ and TNF expression after incubation with Gp33 peptide ex vivo on day 12 p.i. (n = 5). (b,c) Flow cytometry plots and quantification of SATB1-KO or control TPEX cells (b) and TEX cells. (c) producing IFN-γ or co-producing IFN-γ and TNF after incubation with Gp33 peptide ex vivo on days 12 (n = 5) and 21 (n = 4) p.i. (d,e) Histogram and quantification showing expression of GzmB (d) and PD-1 (e) in SATB1-KO or control TEX cells on day 12 p.i (n = 8). (f) Expression of PD-1 on SATB1-KO and control P14 cells after 66 h of in vitro stimulation (n = 10). (g) Expression of TOX in SATB1-KO or control P14 cells from day 12 of LCMV-Docile infection (n = 8). (h) Viral load in the lungs and kidneys of SATB1-KO or control mice infected with LCMV-Docile on day 31 p.i. (n = 3). Flow cytometry plots are representative. Dots in graphs represent biological replicates; horizontal lines and error bars of bar graphs indicate means ± SEM (a-g) or SD (h), respectively. Data are representative (a-c, h) or pooled from two (d-g) independent experiments. P values are from two-tailed unpaired student’s t test. PFU, Plaque forming units.

Extended Data Fig. 3 SATB1 downregulation is required for TEX cell differentiation.

(a) Schematic illustrating the generation of Rosa26Satb1 locus allele. A lox-STOP-lox cassette followed by an Satb1-IRES-GFP sequence was inserted downstream of the CAG promoter region on the Rosa26 gene locus. Cre-mediates deletion of the STOP-codon leads to continuously expression of Satb1-GFP. (b-g) Mixed bone marrow chimeric mice containing Satb1Tg (CD45.2+) and control T cells (CD45.1/2+) were infected with LCMV-Docile. Spleens were harvested on day 12 and 21 p.i. and analyzed using flow cytometry. (b) Flow cytometry plots and quantification on day 12 p.i. showing frequencies of activated CD44+ and exhausted PD-1+ Satb1Tg or control cells (n = 14). (c) Quantification on day 12 p.i. of CD44 (n = 9) and PD-1 (n = 14) expression among PD-1+ Satb1Tg or control cells. (d) Normalized numbers of Satb1Tg or control TPEX and TEX cells on day 21 p.i (n = 9). (e) Flow cytometry plots and quantification of Satb1Tg or control TPEX and TEX cells from Day 12 p.i (n = 14). (f,g) Expression of TCF1 (n = 10) and Ly108 (n = 15) (f) and PD-1 (n = 14), TOX (n = 9), and CD44 (n = 13) (g) in Satb1Tg or control TPEX cells from day 21 p.i. (h) Flow cytometry plots and quantification on days 12 (n = 9) and 21 (n = 14) p.i. showing frequencies of Satb1Tg and control CD62L+ TPEX cells. Flow cytometry plots are representative. Dots in graphs represent individual mice; horizontal lines and error bars of bar graphs indicate means ± SEM, respectively. Data are pooled from two (c) or three (b,d-g) independent experiments. P values are from two-tailed paired student’s t test.

Extended Data Fig. 4 SATB1 expression is required for efficient cytokine production.

Mixed bone marrow chimeric mice containing Satb1Tg (CD45.2+) and control T cells (CD45.1/2+) were infected with LCMV-Docile. On days 12 and 21 p.i. spleens were analyzed using flow cytometry. (a) Quantification of PD-1 expression on day 12 p.i. (n = 9) and 21 p.i. (n = 8), and of TOX (n = 4) expression on day 21 in Gp33+ Satb1Tg or control cells. (b) Flow cytometry plots and quantification on day 21 p.i. showing frequencies of Satb1Tg or control TPEX and TEX cells among Gp33+ cells (n = 9). (c-e) Flow cytometry plots and quantification of IFN-γ (n = 13) and TNF (n = 11) production from TPEX (c) and TEX (n = 13) (d,e) cells after incubation of Satb1Tg or control CD8 T cells with Gp33 peptide on day 21 p.i. (f) Flow cytometry plots and quantification of IFN-γ and TNF production from Satb1Tg or control PD-1+ CD8 T cells after incubation with PMA/Ionomycin (n = 8). (g-l) CTV-labelled SATB1-KO and control P14 cells were adoptively transferred to recipient mice prior to infection with chronic LCMV-Clone13 before analysis on day 3 p.i. (g) Outline of experimental scheme. (h) Flow cytometry plot of control cells and quantification of SATB1 expression per cell division (n = 5). (i) Histogram and quantification of frequencies of TCF1+ SATB1-KO and control P14 cells per cell division (n = 5). (j) Histogram and quantification of frequencies of CD62L+ SATB1-KO and control P14 cells per cell division (n = 5). (k) Quantification of PD-1 expression on SATB1-KO and control P14 cells per cell division (n = 5). (l) Flow cytometry plots and quantification of KLRG1 expression on SATB1-KO and control P14 cells in divisions 6 and >7 (n = 5). Flow cytometry plots are representative. Data are representative (h-l) or pooled (a-c) from two or three (d-f) independent experiments. Dots in graphs represent individual mice; horizontal lines and error bars represent indicate means ± SEM, respectively. P values in (a-f) are from two-tailed paired student’s t test.

Extended Data Fig. 5 SATB1 expression is repressed by TGF-β and limits differentiation of short-lived effect CD8+ T cells.

(a) Histogram and quantification of SATB1 expression in wild-type CD8+ T cells that were stimulated in vitro in the presence or absence of titrated doses of TGF-β (n = 8). (b-d) Mixed bone marrow chimeric mice containing TGF-βR2 deficient and control CD8+ T cells were infected with LCMV-Docile. Spleens were analyzed on day 21 p.i. by flow cytometry. (b) Schematic of experimental set up. (c) SATB1 expression in TGF-βR2 deficient and control Gp33-specific CD8+ T cells (n = 10). (d) SATB1 expression in TGF-βR2 deficient and control Gp33-specific CD8+ T cell subsets (n = 10). (e,f) Naïve CD45.1+ P14 cells were adoptively transferred into naïve wildtype CD45.2+ mice and infected with LCMV-Armstrong. Spleens were harvested on days 7 or 28 p.i. and analyzed using flow cytometry. (e) Quantification showing the expression of SATB1 in MPC and SLEC cells compared to naïve CD8+ T cells and B cells (n = 10). (f) Histograms and quantification showing the expression of SATB1 in TCM and TEM cells compared to naïve CD8+ T cells and B cells (n = 9). (g-n) Naïve CD45.2+ SATB1-deficient P14 cells (Satb1flex/flex/Cd8Cre, SATB1-KO) or control cells (Satb1flex/flex) P14 cells were adoptively transferred into naïve wildtype CD45.1+ mice and subsequently infected with LCMV-Armstrong. Mice were analyzed on day 7 p.i. (g) Schematic of experimental set up. (h,i) Flow cytometry plots (h) and quantification (i) of SATB1-KO and control P14 frequencies and numbers per spleen (n = 10). (j) Flow cytometry plots and quantification showing TIM-3 and PD-1 expression in SATB1-KO and control splenic P14 cells (n = 10). (k) Quantification of SATB1-KO and control SLEC and MPC numbers per spleen (n = 10). (l) Flow cytometry plots of IFN-γ and TNF production from SATB1-KO or control SLEC and MPC cells after incubation with Gp33 peptide (n = 10). (m) Quantification of frequencies of IFN-γ and TNF producing SATB1-KO and control SLEC and MPC (n = 10). (n) Quantification of IFN-γ and TNF expression in SATB1-KO and control SLEC and MPC (n = 10). Flow cytometry plots are representative. Dots in graphs represent biological replicates; horizontal lines and error bars of graphs indicate means and SD respectively (a). Data are pooled from at least two experiments. Dots in graphs represent individual mice (c-n); horizontal lines and error bars of bar graphs indicate means ± SEM, respectively. P values are from unpaired, two-way ANOVA (e,f), or two-tailed paired student’s t-tests (c,d). P values are from unpaired student’s t test (a,i-n).

Extended Data Fig. 6 SATB1 downregulation is required for proper effector differentiation in acute viral infection.

(a-c) Naïve CD45.1+ P14 cells were adoptively transferred into naïve wildtype CD45.2+ mice and infected with LCMV-Armstrong. Spleens were harvested on days 7 or 28 p.i. and analyzed using flow cytometry. (a) Flow cytometry plots and quantification of SATB1-KO and control CX3CR1 and KLRG1 SLEC populations on day 7 p.i. (n = 10). (b) Histogram and quantification of GzmB producing SATB1-KO or control SLEC on day 7 p.i. (n = 10). (c) Quantification of SATB1-KO (n = 9) and control (n = 10) TCM and TEM cell numbers per spleen on day 28 p.i. (d-g) Mixed bone marrow chimeric mice containing Satb1Tg (CD45.2+) and control T cells (CD45.1/2+) were infected with LCMV-Armstrong. On day 7 p.i. spleens were analyzed using flow cytometry. (d) Flow cytometry plots and quantification of activated CD44+ Satb1Tg and control cells (n = 10). (e) Quantification of PD-1 expression in PD-1+ and Gp33+ Satb1Tg and control cells (n = 10). (f) Flow cytometry plots and quantification of CX3CR1 and KLRG1 Gp33+ Satb1Tg and control populations (n = 10). (g) Quantification of cytokine expression Satb1Tg and control cells after Gp33 peptide restimulation (n = 10). Flow cytometry plots are representative. Dots in graphs represent individual mice; horizontal lines and error bars of bar graphs indicate means ± SEM, respectively. Data are pooled from two independent experiments. P values are from two-tailed paired student’s t test.

Extended Data Fig. 7 Loss of SATB1 does not impact exhausted T cell subset specific chromatin accessibility.

Naïve CD45.2+ SATB1-deficient P14 cells (Satb1flex/flex/Cd8Cre, SATB1-KO) or control cells (Satb1flex/flex) P14 cells were adoptively transferred into naïve wildtype CD45.1+ mice which were subsequently infected with LCMV-Docile. On 21 p.i., CD62L+ and CD62L− TPEX and CX3CR1+ and CD101+ TEX cells were sorted from either SATB1-KO or control spleens and used for RNA and ATAC-sequencing. (a) Comparison of gene accessibility in control CD62L+ TPEX, CD62L− TPEX, CX3CR1+ TEX and CD101+ TEX cells. TCF7, Irf4, Slamf1 and Tgfbr2 are shown as examples. (b) Representation of the first two components of a PCA dimensionality reduction based on rlog-transformed counts for all accessible peaks. First component explains 56% and second component explains 19% of total variability. Cell type and genotypes are color coded. (c) K-means clustered heatmap showing normalized counts of all peaks identified using the nextflow pipeline nf-core/atacseq v1.2.1. TPEX and TEX cell subsets, genotype and replicates are color coded and shown as bars at the top of the heatmap. (d) Proportion of open chromatin peaks identified by ATAC-seq that overlap with SATB1 binding sites as identified by ChIP-seq. (e) Volcano plots showing genes associated with differentially accessible regions (DARs). DARs were identified using the nextflow pipeline nf-core/atacseq v1.2.1, which passed the False Discover Rate (FDR) < 0.05. Genes closest to the respective DAR were identified using Homer v4.11. Each volcano plot shows a SATB1-KO vs Ctrl comparison for each TPEX and TEX cell subset. Dashed lines: reciprocal adjusted p-value < 0.01 (padj−1 vertical) and log2 fold change (log2FC) > 1.5 (horizontal). Statistical significance is color coded by passing log2FC and padj−1 cut-offs (red), passing only log2FC- (green) or padj−1 cut-off (blue). Top genes were labelled with the gene name. (f) Volcano plot showing accessible regions in the Ifng, Tnf and Gzmb gene loci. The Gzmb transcriptional start site is highlighted in red. (g) GOEA analysis of genes associated with differentially accessible regions. DARs were used for Gene Ontology Enrichment Analysis (GOEA) using the Hallmark gene sets from the GSEA-MSigDB database as reference. Ontology terms were filtered for an adjusted p-value < 0.05. Each Hallmark term is indicated as the main bubble surrounded by genes belonging to the term. Number of genes belonging to a term is indicated by bubble size. Comparison to identify DARs is indicated by color. Shared terms between comparisons are colored by multiple colors.

Extended Data Fig. 8 SATB1 binds to genomic regions that show differential accessibility during exhausted T cell differentiation.

(a-c) Naïve CD45.2+ SATB1-deficient P14 cells (Satb1flex/flex/Cd8Cre, SATB1-KO) or control cells (Satb1flex/flex) P14 cells were adoptively transferred into naïve wildtype CD45.1+ mice which were subsequently infected with LCMV-Docile. On 21 p.i., CD62L+ and CD62L− TPEX and CX3CR1+ and CD101+ TEX cells were sorted from either SATB1-KO or control spleens and used for RNA and ATAC-sequencing. Shown are SATB1 ChIP binding and gene accessibility in indicated cell types. (a) Ifng, (b) Slamf1, Slamf6, and (c) Arid5a, Ccr5 and Prdm1. (d-i) Mixed bone marrow chimeric mice containing SATB1-DNA-binding mutant (Satb1m1Anu/m1Anu) (CD45.2+) and control T cells (CD45.1/2+) were infected with LCMV-Docile. On day 21 p.i. spleens were analyzed using flow cytometry. (d) Flow cytometry plots and quantification showing frequencies of activated Gp33+ Satb1m1Anu/m1Anu or control cells. (e) Flow cytometry plots and quantification showing frequencies of Satb1m1Anu/m1Anu or control TPEX and TEX cells. (f) Expression of TCF1 and Ly108 in Gp33+ Satb1m1Anu/m1Anu or control TPEX cells. (g) Flow cytometry plots and quantification showing frequencies of Satb1m1Anu/m1Anu or control CD62L+ TPEX cells. (h) Flow cytometry plots and quantification showing frequencies of Satb1m1Anu/m1Anu or control CX3CR1+ and CD101+ TEX cells. (i) Flow cytometry plots and quantification showing frequencies of IFN-γ and TNF producing Satb1m1Anu/m1Anu or control cells after stimulation with Gp33 peptide ex vivo. Flow cytometry plots are representative. Dots in graphs represent individual mice; horizontal lines and error bars of bar graphs indicate means ± SEM, respectively. Data are pooled from two independent experiments. P values are from two-tailed unpaired student’s t test.

Extended Data Fig. 9 SATB1 limits tumor control and response to checkpoint inhibition.

Naïve CD45.2+ SATB1-deficient P14 cells (Satb1flex/flex/Cd8Cre, SATB1-KO) or control cells (Satb1flex/flex) P14 cells were adoptively transferred into naïve wildtype CD45.1+ mice 3 days after inoculation with B16/Gp33+ Tumor cells. Mice were treated with immune checkpoint blockade (ICB, anti-PDL-1 + anti-CTLA4) or PBS. (a,b) Tumor growth (a) and survival (b) of mice transferred with either SATB1-KO or control P14 cells treated with or without ICB (n = 8). Data are pooled from two independent experiments. (c,d) Representative flow cytometry plots and quantification showing the frequencies of IFN-γ and TNF producing SATB1-KO and Control P14 cells in the tumor (c) and tdLNs (d) treated with or without ICB after ex vivo restimulation with Gp33 peptide (untreated n = 8, treated KO n = 5, treated WT n = 7). Dots in graphs represent individual mice; horizontal lines and error bars of bar graphs indicate means ± SEM, respectively. Data are pooled from two independent experiments. P values are from two-way ANOVA (b) or unpaired student’s t test (c,d).

Extended Data Fig. 10 SATB1 limits effector differentiation of CD8+ T cells in tumor draining lymph nodes.

Naïve CD45.2+ SATB1-deficient P14 cells (Satb1flex/flex/Cd8Cre, SATB1-KO) or control cells (Satb1flex/flex) P14 cells were adoptively transferred into naïve wildtype CD45.1+ mice 3 days after inoculation with B16/Gp33 tumor cells. Mice were treated with immune checkpoint blockade (ICB, anti-PDL-1 + anti-CTLA4) or PBS on indicated days. Tumor draining LN (tdLNs) were harvested on day 16 after inoculation and analyzed using flow cytometry. (a) Representative flow cytometry plots and quantification showing frequencies and numbers of SATB1-KO or control P14 cells (untreated n = 8, treated KO n = 6, treated WT n = 7). (b) Representative flow cytometry plots and quantification showing frequencies and numbers SATB1-KO or control CX3CR1+ TEX cells (untreated n = 8, treated KO n = 6, treated WT n = 7). (c) Representative flow cytometry plots and quantification showing frequencies and numbers of GzmB producing SATB1-KO or control P14 cells (untreated n = 8, treated KO n = 6, treated WT n = 7). Dots in graphs represent individual mice; horizontal lines and error bars of bar graphs indicate means ± SEM, respectively. Data are representative of two independent experiments. P values are from unpaired student’s t test.

Supplementary information

Supplementary Information

Supplementary Figs. 1–3.

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Supplementary Table 1

ATAC DARs, cell-type specific, FDR_0_05_LFC_1_5.

Supplementary Table 2

ATAC DARs, genotype specific, KOvsWT_FDR_0_1.

Supplementary Table 3

Venn diagram related to Fig. 6f.

Supplementary Table 4

Differentially expressed genes between wild-type and Satb1 KO.

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Heyden, L., Rausch, L., Shannon, M.H. et al. Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer. Nat Immunol (2025). https://doi.org/10.1038/s41590-025-02316-2

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