AFF3 maintains metabolic quiescence in naive CD8 T cells and prevents premature immune aging
Molly E. Lumnitzer, Stefanie F. Valbon, Stephanie A. Condotta, Allison E. Norlander, Sheng Liu, Jun Wan, Martin J. Richer
Molly E. Lumnitzer, Stefanie F. Valbon, Stephanie A. Condotta, Allison E. Norlander, Sheng Liu, Jun Wan, Martin J. Richer
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Research Article Aging Immunology Metabolism

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

Abstract

It is necessary for naive 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 naive CD8 T cells. While naive 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 identify a transcription factor that may be a target to reinvigorate CD8 T cell responses during aging.

Authors

Molly E. Lumnitzer, Stefanie F. Valbon, Stephanie A. Condotta, Allison E. Norlander, Sheng Liu, Jun Wan, Martin J. Richer

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Figure 1

Aff3 is decreased with inflammation and necessary for a robust T cell response to viral infection.

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Aff3 is decreased with inflammation and necessary for a robust T cell re...
(A) Heatmap of the top 15 differentially expressed genes in OT-I CD8 T cells from the spleen of DC-OVA or DC-OVA + LCMV immunized mice on day 5 compared with naive OT-I CD8 T cells identified by microarray. (B) Relative mRNA expression of Aff3 from OT-I CD8 T cells isolated from the spleen of DC-OVA or DC-OVA + LCMV immunized mice by RT-qPCR analysis compared with normalized expression in naive OT-I CD8 T cells. (C) Relative mRNA expression of Aff3 from CD8 T cells isolated from the spleens WT, AFF3 heterozygous (Het), and AFF3 KO mice by RT-qPCR analysis. (D) Frequency of splenic WT or AFF3 KO P14 CD8 T cells at input, or from the spleen 3 dpi, 5 dpi, and 8 dpi with LCMV Arm. (E and F) Number of WT or AFF3 KO P14 CD8 T cells in the spleen at 5 dpi and 8 dpi with LCMV Arm. (G) Expansion ratio of WT and AFF3 KO P14 CD8 T cells from 5 to 8 dpi with LCMV Arm. (H) Representative histogram plots of the dilution of TagIT Violet proliferation dye by splenic WT and AFF3 KO CD8 T cells on days 0–3 of ex vivo culture. (A) Pooled CD8 T cells from 1–3 mice with 3 replicates per condition and representative of at least 2 separate experiments. (B and C) Pooled CD8 T cells from 1–3 mice in each condition. (D–H) Representative of 2 experiments with n = 3–5 mice per experiment. (D–G) Groups compared using paired Student’s t test, *P < 0.05, ***P < 0.001. Data represent mean ± SEM.