Journal Article

DZNE-2025-01318

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer.

Heyden, L. ; Rausch, L. ; Shannon, M. H. ; Dryburgh, L. ; Moreira, M. L. ; Frolov, A.DZNE* ; Scheffler, C. M. ; van Elsas, M. J. ; Tong, J. ; Hidajat, O. ; Wijesinghe, S. K. M. ; Li, S. ; Horvatic, H. ; Huynh-Anh, N. T. ; Gago da Graça, C. ; Tsui, C. ; Köhne, M.DZNE* ; Sommer, D. ; Wunderlich, F. T. ; von Scheidt, B. ; Park, S. L. ; Mackay, L. K. ; Utzschneider, D. T. ; Schröder, J. ; Turner, S. J. ; Darcy, P. K. ; Beyer, M. D.DZNE* ; Abdullah, Z. ; Kallies, A.

2025
Springer Nature Limited London

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Please use a persistent id in citations: doi:10.1038/s41590-025-02316-2

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.

Keyword(s): Matrix Attachment Region Binding Proteins: metabolism (MeSH) ; Matrix Attachment Region Binding Proteins: genetics (MeSH) ; Matrix Attachment Region Binding Proteins: immunology (MeSH) ; CD8-Positive T-Lymphocytes: immunology (MeSH) ; Animals (MeSH) ; Cell Differentiation: immunology (MeSH) ; Mice (MeSH) ; Immunologic Memory (MeSH) ; Mice, Inbred C57BL (MeSH) ; Neoplasms: immunology (MeSH) ; Humans (MeSH) ; Persistent Infection: immunology (MeSH) ; Lymphocytic Choriomeningitis: immunology (MeSH) ; Mice, Knockout (MeSH) ; Cell Proliferation (MeSH) ; Lymphocytic choriomeningitis virus: immunology (MeSH) ; Matrix Attachment Region Binding Proteins ; Satb1 protein, mouse ; SATB1 protein, human

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Contributing Institute(s):

1. Immunogenomics and Neurodegeneration (AG Beyer)
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
3. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
3. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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