The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation
During persistent antigen stimulation, exhausted CD8<sup>+</sup> T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8<sup>+</sup> T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell-intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8<sup>+</sup> T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8<sup>+</sup> GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8<sup>+</sup> T cells and long-term T cell immunity during chronic antigen exposure.
Authors
- Andrew DeVilbiss (ORCID: https://orcid.org/0000-0002-9739-2543)
- Taidou Hu (ORCID: https://orcid.org/0000-0003-1520-7824)
- Safuwra Wizzard (ORCID: https://orcid.org/0000-0003-1107-8789)
- Ralph J. DeBerardinis (ORCID: https://orcid.org/0000-0002-2705-7432)
- Ziang Zhu (ORCID: https://orcid.org/0009-0008-4231-7213)
- S Shinde
- Chaoyu Ma
- Sarah Muh
- Guohua Lou (ORCID: https://orcid.org/0000-0002-2829-3429)
- Ying Luo (ORCID: https://orcid.org/0000-0002-1325-2296)
- Jonathan Hoar
- Tuoqi Wu (ORCID: https://orcid.org/0000-0002-4003-1034)
- Kiddist Yihunie (ORCID: https://orcid.org/0000-0002-0863-4863)
- Nu Zhang (ORCID: https://orcid.org/0000-0001-9695-210X)
- Chen Yao (ORCID: https://orcid.org/0000-0001-6852-5661)
- Sandip Biswal (ORCID: https://orcid.org/0009-0000-5794-3403)
Institutions
- Children's Medical Center (US)
- Bloomberg (United States) (US)
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Johns Hopkins Medicine (US)
- Southwestern Medical Center (US)
- South Texas Veterans Health Care System (US)
- University of Colorado Anschutz Medical Campus (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1126/sciimmunol.adk2954
- Citations
- 19
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 4.57
Funders
- Cancer Research Institute
- Cancer Prevention and Research Institute of Texas
- University of Texas Southwestern Medical Center
- National Institutes of Health