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

Heyden, L; Rausch, L; Shannon, MH; Dryburgh, L; Moreira, ML; Frolov, A; Scheffler, CM; van Elsas, MJ; Tong, J; Hidajat, O; Wijesinghe, SKM; Li, S; Horvatic, H; Huynh-Anh, NT; Gago da Graca, C; Tsui, C; Kohne, M; Sommer, D; Wunderlich, FT; von Scheidt, B; Park, SL; Mackay, LK; Utzschneider, DT; Schroder, J; Turner, SJ; Darcy, PK; Beyer, MD; Abdullah, Z; Kallies, A

Author(s): Heyden, L; Rausch, L; Shannon, MH; Dryburgh, L; Moreira, ML; Frolov, A; Scheffler, CM; van Elsas, MJ; Tong, J; Hidajat, O; Wijesinghe, SKM; Li, S; Horvatic, H; Huynh-Anh, NT; Gago da Graca, C; Tsui, C; Kohne, M; Sommer, D; Wunderlich, FT; von Scheidt, B; Park, SL; Mackay, LK; Utzschneider, DT; Schroder, J; Turner, SJ; Darcy, PK; Beyer, MD; Abdullah, Z; Kallies, A;
Details: Publication Year 2025-12,Volume 26,Issue #12,Page 2312-2327
Journal Title: Nature Immunology
Publication Type: Research article
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 (T(PEX)) 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 T(PEX) cells where it limited population expansion and effector differentiation while preserving functionality of CD8(+) T cells. SATB1 downregulation was required for T(PEX) 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.
Keywords: *Matrix Attachment Region Binding Proteins/metabolism/genetics/immunology; *CD8-Positive T-Lymphocytes/immunology; Animals; Cell Differentiation/immunology; Mice; Immunologic Memory; Mice, Inbred C57BL; *Neoplasms/immunology; Humans; *Persistent Infection/immunology; *Lymphocytic Choriomeningitis/immunology; Mice, Knockout; Cell Proliferation; Lymphocytic choriomeningitis virus/immunology
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41590-025-02316-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-12-04 05:58:03

Last Modified: 2025-12-04 05:59:00