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 5

IL-15 promotes proliferation of CCR7–CX3CR1+CD57+CD28–CD8+ Tmem via STAT5 and mTORC1 activity.

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IL-15 promotes proliferation of CCR7–CX3CR1+CD57+CD28–CD8+ Tmem via STAT...
(A) Representative labeling with CellTrace Violet and quantification of proliferation after 7 days of stimulation expressed as FC over medium control in sorted CCR7–CX3CR1+CD57+CD28–CD8+ Tmem from CMV+ PLWH (n = 4–15/stim), gated on viable cells. Data represent median ± IQR. Significance determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons. (B) Proliferation after 7 days of stimulation with medium control or IL-15 with or without indicated inhibitors in sorted CCR7–CX3CR1+CD57+CD28–CD8+ Tmem gated on viable cells from CMV+ PLWH (n = 8–14/stim). Data represent median ± IQR. Significance determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons. (C) Summary of viability and proliferation outcomes. (D) STAT5 pY694 and S6 pS240 expression 45 minutes after stimulation with medium control or IL-15 with or without indicated inhibitors in gated CD57+CD8+ T cells from CMV+ PLWH (n = 9). Data represent median ± IQR. Significance determined by Kruskal-Wallis test with Dunn’s correction for multiple comparisons. (E) MitoTracker Green and MitoTracker Orange labeling expressed as FC over medium control in CD57+CD8+ T cells from CMV+ PLWH (n = 9) after 4 days stimulation with IL-15 with or without rapamycin (Rapa). Significance determined by Wilcoxon’s matched-pairs test.