TY - JOUR
T1 - IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection
AU - Younes, Souheil Antoine
AU - Freeman, Michael L.
AU - Mudd, Joseph C.
AU - Shive, Carey L.
AU - Reynaldi, Arnold
AU - Panigrahi, Soumya
AU - Estes, Jacob D.
AU - Deleage, Claire
AU - Lucero, Carissa
AU - Anderson, Jodi
AU - Schacker, Timothy W.
AU - Davenport, Miles P.
AU - McCune, Joseph M.
AU - Hunt, Peter W.
AU - Lee, Sulggi A.
AU - Serrano-Villar, Sergio
AU - Debernardo, Robert L.
AU - Jacobson, Jeffrey M.
AU - Canaday, David H.
AU - Sekaly, Raafick Pierre
AU - Rodriguez, Benigno
AU - Sieg, Scott F.
AU - Lederman, Michael M.
N1 - Funding Information:
We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of the tetramers. This work was supported by grant awards AI105937 and AI68636 from the NIAID; the Fasenmyer Foundation; NIAID grant award AI36219; and the Case Western Reserve University Center for AIDS Research. This project has been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI85996
DO - 10.1172/JCI85996
M3 - Article
C2 - 27322062
AN - SCOPUS:84978374839
SN - 0021-9738
VL - 126
SP - 2745
EP - 2756
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -