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

TitleIL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection.
Publication TypeJournal Article
Year of Publication2016
AuthorsYounes S-A, Freeman ML, Mudd JC, Shive CL, Reynaldi A, Panigrahi S, Estes JD, Deleage C, Lucero C, Anderson J, Schacker TW, Davenport MP, McCune JM, Hunt PW, Lee SA, Serrano-Villar S, Debernardo RL, Jacobson JM, Canaday DH, Sekaly R-P, Rodriguez B, Sieg SF, Lederman MM
JournalJ Clin Invest
Volume126
Issue7
Pagination2745-56
Date Published2016 Jul 01
ISSN1558-8238
KeywordsAdult, Aged, Animals, Anti-Retroviral Agents, Biopsy, Case-Control Studies, CD8-Positive T-Lymphocytes, Cell Proliferation, Female, Granzymes, Haplotypes, HIV Infections, HIV-1, Humans, Interleukin-15, Ki-67 Antigen, Leukocyte Common Antigens, Leukocytes, Mononuclear, Lymph Nodes, Lymphocyte Activation, Male, Mice, Middle Aged, Phenotype, Receptors, CCR7
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.

DOI10.1172/JCI85996
Alternate JournalJ. Clin. Invest.
PubMed ID27322062
PubMed Central IDPMC4922693
Grant ListHHSN272201300006C / AI / NIAID NIH HHS / United States
T32 AI089474 / AI / NIAID NIH HHS / United States
U01 AI105937 / AI / NIAID NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
P30 AI036219 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States