Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15
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
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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Research Article AIDS/HIV Immunology

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

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 3

IL-15 promotes CX3CR1 and CD57 expression and mitochondrial activity in CD8+ Tmem.

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IL-15 promotes CX3CR1 and CD57 expression and mitochondrial activity in ...
(A) Representative histograms and quantification of CX3CR1 and CD57 expression 48 hours after indicated stimulation expressed as fold change (FC) over medium control on CD8+ Tmem from CMV+ PLWH (n = 6). Data represent median ± IQR. Significance determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons. (B) Representative histograms and quantification of CX3CR1, CD57, and CD28 expression on sorted CD8+ central memory T cells (Tcm) from CMV+ PLWH (n = 6) 7 days after IL-15 stimulation, expressed as FC over medium control. Data represent median ± IQR. Significance determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons. (C–F) Representative histograms from day 4 of stimulation and quantification of forward scatter (FSC-A) (C), MitoTracker Green (D), MitoTracker Orange (E), and intracellular c-myc (F) 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, IL-15 versus IL-2; #P ≤ 0.05, ##P ≤ 0.01, TCR versus IL-2; %P ≤ 0.05, IL-15 versus TCR. Significance within groups (7 days vs. 1 day) determined by Wilcoxon’s matched-pairs test: *P ≤ 0.05.