TY  - JOUR
AU  - Heyden, Leonie
AU  - Rausch, Lisa
AU  - Shannon, Michael H
AU  - Dryburgh, Lachlan
AU  - Moreira, Marcela L
AU  - Frolov, Aleksej
AU  - Scheffler, Christina M
AU  - van Elsas, Marit J
AU  - Tong, Junming
AU  - Hidajat, Olivia
AU  - Wijesinghe, Sharanya K M
AU  - Li, Sining
AU  - Horvatic, Helena
AU  - Huynh-Anh, Nhat Truong
AU  - Gago da Graça, Catarina
AU  - Tsui, Carlson
AU  - Köhne, Maren
AU  - Sommer, Daniel
AU  - Wunderlich, F Thomas
AU  - von Scheidt, Bianca
AU  - Park, Simone L
AU  - Mackay, Laura K
AU  - Utzschneider, Daniel T
AU  - Schröder, Jan
AU  - Turner, Stephen J
AU  - Darcy, Phillip K
AU  - Beyer, Marc D
AU  - Abdullah, Zeinab
AU  - Kallies, Axel
TI  - Transcriptional regulator SATB1 limits CD8+ T cell population expansion and effector differentiation in chronic infection and cancer.
JO  - Nature immunology
VL  - 26
IS  - 12
SN  - 1529-2908
CY  - London
PB  - Springer Nature Limited
M1  - DZNE-2025-01318
SP  - 2312 - 2327
PY  - 2025
AB  - 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.
KW  - Matrix Attachment Region Binding Proteins: metabolism
KW  - Matrix Attachment Region Binding Proteins: genetics
KW  - Matrix Attachment Region Binding Proteins: immunology
KW  - CD8-Positive T-Lymphocytes: immunology
KW  - Animals
KW  - Cell Differentiation: immunology
KW  - Mice
KW  - Immunologic Memory
KW  - Mice, Inbred C57BL
KW  - Neoplasms: immunology
KW  - Humans
KW  - Persistent Infection: immunology
KW  - Lymphocytic Choriomeningitis: immunology
KW  - Mice, Knockout
KW  - Cell Proliferation
KW  - Lymphocytic choriomeningitis virus: immunology
KW  - Matrix Attachment Region Binding Proteins (NLM Chemicals)
KW  - Satb1 protein, mouse (NLM Chemicals)
KW  - SATB1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41145844
DO  - DOI:10.1038/s41590-025-02316-2
UR  - https://pub.dzne.de/record/282555
ER  -