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

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 1

Increased cycling of CD45RO+ CD8+ T cells in viremic HIV-1 infection.

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Increased cycling of CD45RO+ CD8+ T cells in viremic HIV-1 infection. (A...
(A) Percentages of Ki-67+ CD3+CD8+ cells among healthy donors (n = 7), healthy elderly donors (n = 10), HIV-1+ viremic subjects (n = 20), ART-treated immune success (IS) patients (n = 12), and ART-treated immune failure (IF) (n = 10) patients. (B) Representative dot plots showing that Ki-67+ CD8+ cells are predominantly found within the CD45RO+CCR7– effector memory–phenotype CD8+ T cell subset. (C) Proportions of cycling Ki-67+ CD8+ T cells in central (CM) (CCR7+CD45RO+), effector (EM) (CCR7–CD45RO+), and terminally differentiated (TD) (CCR7–CD45RO–) memory populations in 7 healthy controls (white symbols) and 13 HIV-1–infected viremic patients (black symbols). (D) Expression of CCR7, CD45RO, and granzyme B among total peripheral blood CD8+ T cells in healthy controls (n = 7, white bars) and HIV-1–infected viremic patients (n = 20, black bars). **P < 0.01, ***P < 0.001 by Kruskal-Wallis test.