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ResearchIn-Press PreviewAgingImmunologyMetabolism Open Access | 10.1172/jci.insight.207387

AFF3 maintains metabolic quiescence in naïve CD8 T cells and prevents premature immune aging

Molly E. Lumnitzer,1 Stefanie F. Valbon,2 Stephanie A. Condotta,1 Allison E. Norlander,3 Sheng Liu,3 Jun Wan,3 and Martin J. Richer1

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, United States of America

2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

3IU Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America

Find articles by Lumnitzer, M. in: PubMed | Google Scholar

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, United States of America

2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

3IU Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America

Find articles by Valbon, S. in: PubMed | Google Scholar

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, United States of America

2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

3IU Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America

Find articles by Condotta, S. in: PubMed | Google Scholar

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, United States of America

2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

3IU Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America

Find articles by Norlander, A. in: PubMed | Google Scholar |

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, United States of America

2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

3IU Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America

Find articles by Liu, S. in: PubMed | Google Scholar

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, United States of America

2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

3IU Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America

Find articles by Wan, J. in: PubMed | Google Scholar |

1Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, United States of America

2Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Canada

3IU Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, United States of America

Find articles by Richer, M. in: PubMed | Google Scholar

Published June 23, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.207387.
Copyright © 2026, Lumnitzer et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 23, 2026 - Version history
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Abstract

It is necessary for naïve CD8 T cells to be actively maintained in a quiescent metabolic state in order to respond robustly to infection while avoiding inappropriate activation during homeostasis. With age this quiescent state is lost and the CD8 T cell response to infection decreases. The factors regulating metabolic quiescence of CD8 T cells and how this regulation is lost during aging are not completely understood. Herein, we identify the transcription factor AFF3 as a regulator of metabolic quiescence in naïve CD8 T cells. While naïve AFF3 deficient CD8 T cells are more metabolically active prior to infection, they have reduced accumulation in response to viral infection, and this is correlated with a poor capacity to engage glycolysis. During aging in both murine and human CD8 T cells, AFF3 expression is decreased. In mice, this is associated with a loss of metabolic quiescence and reduced capacity to accumulate following infection. Our data highlight the role of metabolic regulation in CD8 T cell quiescence and identifies a transcription factor that may be a target to reinvigorate CD8 T cell responses during aging.

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  • Version 1 (June 23, 2026): In-Press Preview
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