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; Raafick Pierre Sekaly; Benigno Rodriguez; Scott F. Sieg; Michael M. Lederman

doi:10.1172/JCI85996

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, Raafick Pierre SekalyBenigno Rodriguez, Scott F. Sieg, Michael M. Lederman

Medicine - Infectious Disease and International

Research output: Contribution to journal › Article › peer-review

83 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2745-2756
Number of pages	12
Journal	Journal of Clinical Investigation
Volume	126
Issue number	7
DOIs	https://doi.org/10.1172/JCI85996
State	Published - Jul 1 2016

Bibliographical note

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.

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Younes, S. A., Freeman, M. L., Mudd, J. C., Shive, C. L., Reynaldi, A., Panigrahi, S., Estes, J. D., Deleage, C., Lucero, C., Anderson, J., Schacker, T. W., Davenport, M. P., McCune, J. M., Hunt, P. W., Lee, S. A., Serrano-Villar, S., Debernardo, R. L., Jacobson, J. M., Canaday, D. H., ... Lederman, M. M. (2016). IL-15 promotes activation and expansion of CD8⁺ T cells in HIV-1 infection. Journal of Clinical Investigation, 126(7), 2745-2756. https://doi.org/10.1172/JCI85996

Younes, SA, 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, RP, Rodriguez, B, Sieg, SF & Lederman, MM 2016, 'IL-15 promotes activation and expansion of CD8⁺ T cells in HIV-1 infection', Journal of Clinical Investigation, vol. 126, no. 7, pp. 2745-2756. https://doi.org/10.1172/JCI85996

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title = "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.",

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

note = "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.",

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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.

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AU - McCune, Joseph M.

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AU - Debernardo, Robert L.

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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.

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