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Gfi1 controls the formation of effector-like CD8(+) T cells during chronic infection and cancer

Ojo, O. A.
; 
Shen, H.
; 
Ingram, J. T.
; 
Bonner, J. A.
; 
Welner, R. S.
; 
Lacaud, G.
; 
Zajac, A. J.
; 
Shi, L. Z.
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Abstract
During chronic infection and tumor progression, CD8(+) T cells lose their effector functions and become exhausted. These exhausted CD8(+) T cells are heterogeneous and comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues and mechanisms directing subset formation are incompletely understood. Here, we show that growth factor independent-1 (Gfi1) is dynamically regulated in exhausted CD8(+) T cells. During chronic LCMV Clone 13 infection, a previously under-described Ly108(+)CX(3)CR1(+) subset expresses low levels of Gfi1 while other established subsets have high expression. Ly108(+)CX(3)CR1(+) cells possess distinct chromatin profiles and represent a transitory subset that develops to effector-like and terminally-exhausted cells, a process dependent on Gfi1. Similarly, Gfi1 in tumor-infiltrating CD8(+) T cells is required for the formation of terminally differentiated cells and endogenous as well as anti-CTLA-induced anti-tumor responses. Taken together, Gfi1 is a key regulator of the subset formation of exhausted CD8(+) T cells.
Authors
Ojo, O. A.
Shen, H.
Ingram, J. T.
Bonner, J. A.
Welner, R. S.
Lacaud, G.
Zajac, A. J.
Shi, L. Z.
Affiliation
Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Department of Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Department of Hematology & Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Immunology Institute, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Lewisshi@uaBMC.edu. Department of Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Lewisshi@uaBMC.edu. O'Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Lewisshi@uaBMC.edu. Immunology Institute, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Lewisshi@uaBMC.edu. Department of Pharmacology and Toxicology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. Lewisshi@uaBMC.edu.
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Date
2025
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All Paterson Institute for Cancer Research
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Article
Citation
Ojo OA, Shen H, Ingram JT, Bonner JA, Welner RS, Lacaud G, et al. Gfi1 controls the formation of effector-like CD8(+) T cells during chronic infection and cancer. Nature communications. 2025 May 15;16(1):4542. PubMed PMID: 40374625. Pubmed Central PMCID: PMC12081725. Epub 2025/05/16. eng.
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https://christie.openrepository.com/handle/10541/627775
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