IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection
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
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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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 2

T cell receptor Vβ family distributions and CDR3 sequencing among cycling and noncycling memory CD8+ T cells.

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T cell receptor Vβ family distributions and CDR3 sequencing among cyclin...
(A) CD45RO+ CD8+ T cells from a viremic HIV-1–infected patient were stained with reagents A to H having combinations of 3 anti-Vβ antibodies—A (Vβ5.3-PE, Vβ7.1–PE-FITC, Vβ3-FITC), B (Vβ9-PE, Vβ17–PE-FITC, Vβ16-FITC), C (Vβ18-PE, Vβ5.1–PE-FITC, Vβ20-FITC), D (Vβ13.1-PE, Vβ13.6–PE-FITC, Vβ8-FITC), E (Vβ5.2-PE, Vβ2–PE-FITC, Vβ12-FITC), F (Vβ23-PE, Vβ1-PE–FITC, Vβ21.3-PE), G (Vβ11-PE, Vβ22–PE-FITC, Vβ14-FITC), and H (Vβ13.2-PE, Vβ4–PE-FITC, Vβ7.2-FITC)—and enumerated according to intracellular staining for Ki-67 as shown. (B) Correlations among expression of each of the 24 Vβ structures among Ki-67+ and Ki-67– cells were averaged for each patient and each control. Distributions of Vβ expression better correlated between Ki-67+ and Ki-67– populations in the HIV-1+ (n = 9) subjects than among healthy controls (n = 6) by Spearman correlations. (C) Proportions of clones as identified by CDR3 sequencing among sorted noncycling (CD71–, x-axis) and cycling (CD71+, y-axis) memory CD8+ T cell populations in 3 healthy controls (top) and 3 HIV-1–infected patients (bottom). Each dot represents a unique clone identified by CDR3 segment sequencing. Red, blue, and green dots represent the clone frequencies in CD71+, CD71–/CD71+ (shared clones), and CD71– cells, respectively. Analyses were performed using immunoSEQ analyzer software (Adaptive Biotechnologies). (D) Entropy (diversity) measurements in proliferating (CD71+) and nonproliferating (CD71–) memory CD8+ T cells in controls (CNT) and HIV-1–infected subjects (HIV-1).