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IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection
Souheil-Antoine Younes, … , Scott F. Sieg, Michael M. Lederman
Souheil-Antoine Younes, … , Scott F. Sieg, Michael M. Lederman
Published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2745-2756. https://doi.org/10.1172/JCI85996.
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Research Article AIDS/HIV

IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection

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Abstract

In HIV-1–infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1–infected patients. Compared with healthy controls, untreated HIV-1–infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1–infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1–infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients.

Authors

Souheil-Antoine Younes, Michael L. Freeman, Joseph C. Mudd, Carey L. Shive, Arnold Reynaldi, Soumya Panigrahi, Jacob D. Estes, Claire Deleage, Carissa Lucero, Jodi Anderson, Timothy W. Schacker, Miles P. Davenport, Joseph M. McCune, Peter W. Hunt, Sulggi A. Lee, Sergio Serrano-Villar, Robert L. Debernardo, Jeffrey M. Jacobson, David H. Canaday, Rafick-Pierre Sekaly, Benigno Rodriguez, Scott F. Sieg, Michael M. Lederman

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Figure 6

Increased IL-15 expression in LNs of untreated HIV-1–infected patients.

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Increased IL-15 expression in LNs of untreated HIV-1–infected patients.
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(A) Representative IHC images of LN sections obtained from an HIV-1– control subject (left), an HIV-1–infected viremic patient (middle), and an HIV-1–infected ART-suppressed patient (right). IL-15 staining (brown), hematoxylin nuclear counterstain (blue). Scale bar: 100 μM. (B) Summary data (means and SEM) representing percentage surface area of the T cell zone that stained for IL-15 protein in 17 healthy controls, 13 HIV-1 untreated, and 12 HIV-1 ART-treated patients. P values were determined by Kruskal-Wallis test. (C) Spearman correlations between the LN levels of IL-15 and peripheral CD8+ T cell counts in untreated HIV-1–infected patients.
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