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Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15
Stephen R. Morris, … , Michael M. Lederman, Michael L. Freeman
Stephen R. Morris, … , Michael M. Lederman, Michael L. Freeman
Published May 5, 2020
Citation Information: JCI Insight. 2020;5(11):e132963. https://doi.org/10.1172/jci.insight.132963.
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Research Article AIDS/HIV Immunology

Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15

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Abstract

HIV infection is associated with an increase in the proportion of activated CD8+ memory T cells (Tmem) that express CX3CR1, but how these cells are generated and maintained in vivo is unclear. We demonstrate that increased CX3CR1 expression on CD8+ Tmem in people living with HIV (PLWH) is dependent on coinfection with human CMV, and CX3CR1+CD8+ Tmem are enriched for a putatively immunosenescent CD57+CD28– phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1+CD57+CD8+ Tmem in vitro, whereas T cell receptor stimulation leads to their death. IL-15–driven survival is dependent on STAT5 and Bcl-2 activity, and IL-15–induced proliferation requires STAT5 and mTORC1. Thus, we identify mechanistic pathways that could explain how “inflammescent” CX3CR1+CD57+ CD8+ Tmem dominate the overall memory T cell pool in CMV-seropositive PLWH and that support reevaluation of immune senescence as a nonproliferative dead end.

Authors

Stephen R. Morris, Bonnie Chen, Joseph C. Mudd, Soumya Panigrahi, Carey L. Shive, Scott F. Sieg, Cheryl M. Cameron, David A. Zidar, Nicholas T. Funderburg, Souheil-Antoine Younes, Benigno Rodriguez, Sara Gianella, Michael M. Lederman, Michael L. Freeman

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Figure 4

IL-15 promotes viability of CCR7–CX3CR1+CD57+CD28–CD8+ Tmem via STAT5 and Bcl-2 activity.

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IL-15 promotes viability of CCR7–CX3CR1+CD57+CD28–CD8+ Tmem via STAT5 an...
(A) Schematic of flow sorting strategy. (B) Representative labeling with LIVE/DEAD Aqua and quantification of viability after 7 days of stimulation expressed as FC over medium control in sorted CCR7–CX3CR1+CD57+CD28–CD8+ Tmem from CMV+ PLWH (n = 5–17/stim). Data represent median ± IQR. Significance determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons. (C) Representative histograms from day 4 of stimulation and quantification of intracellular Bcl-2 staining after stimulation expressed as FC over medium control in CCR7–CX3CR1+CD57+CD28–CD8+ Tmem from HIV-uninfected controls (n = 7). Data represent median ± IQR. Significance among groups determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons: *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.005, IL-15 versus IL-2; ##P ≤ 0.01, TCR versus IL-2; %P ≤ 0.05, %%P ≤ 0.01, IL-15 versus TCR. Significance within groups (7 days vs. 1 day) determined by Wilcoxon’s matched-pairs test: *P ≤ 0.05. (D) Viability after 7 days of stimulation with medium control or IL-15 with or without indicated inhibitors in sorted CCR7–CX3CR1+CD57+CD28–CD8+ Tmem from CMV+ PLWH (n = 8–14/stim). Data represent median ± IQR. Significance determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons.

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