Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells.

Details

Serval ID
serval:BIB_4DF6A38C551F
Type
Article: article from journal or magazin.
Collection
Publications
Title
Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells.
Journal
Journal of immunology
Author(s)
Porichis F., Hart M.G., Massa A., Everett H.L., Morou A., Richard J., Brassard N., Veillette M., Hassan M., Ly N.L., Routy J.P., Freeman G.J., Dubé M., Finzi A., Kaufmann D.E.
ISSN
1550-6606 (Electronic)
ISSN-L
0022-1767
Publication state
Published
Issued date
01/08/2018
Peer-reviewed
Oui
Volume
201
Number
3
Pages
971-981
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Immune exhaustion is an important feature of chronic infections, such as HIV, and a barrier to effective immunity against cancer. This dysfunction is in part controlled by inhibitory immune checkpoints. Blockade of the PD-1 or IL-10 pathways can reinvigorate HIV-specific CD4 T cell function in vitro, as measured by cytokine secretion and proliferative responses upon Ag stimulation. However, whether this restoration of HIV-specific CD4 T cells can improve help to other cell subsets impaired in HIV infection remains to be determined. In this study, we examine a cohort of chronically infected subjects prior to initiation of antiretroviral therapy (ART) and individuals with suppressed viral load on ART. We show that IFN-γ induction in NK cells upon PBMC stimulation by HIV Ag varies inversely with viremia and depends on HIV-specific CD4 T cell help. We demonstrate in both untreated and ART-suppressed individuals that dual PD-1 and IL-10 blockade enhances cytokine secretion of NK cells via restored HIV-specific CD4 T cell function, that soluble factors contribute to these immunotherapeutic effects, and that they depend on IL-2 and IL-12 signaling. Importantly, we show that inhibition of the PD-1 and IL-10 pathways also increases NK degranulation and killing of target cells. This study demonstrates a previously underappreciated relationship between CD4 T cell impairment and NK cell exhaustion in HIV infection, provides a proof of principle that reversal of adaptive immunity exhaustion can improve the innate immune response, and suggests that immune checkpoint modulation that improves CD4/NK cell cooperation can be used as adjuvant therapy in HIV infection.
Keywords
Anti-Retroviral Agents/pharmacology, CD4-Positive T-Lymphocytes/drug effects, CD4-Positive T-Lymphocytes/immunology, Cell Line, Tumor, Cohort Studies, HIV Infections/drug therapy, HIV Infections/immunology, HIV-1/drug effects, HIV-1/immunology, Humans, Interferon-gamma/immunology, Interleukin-10/immunology, Interleukin-2/immunology, K562 Cells, Killer Cells, Natural/drug effects, Killer Cells, Natural/immunology, Leukocytes, Mononuclear/drug effects, Leukocytes, Mononuclear/immunology, Leukocytes, Mononuclear/virology, Programmed Cell Death 1 Receptor/immunology, Viral Load/drug effects, Viral Load/immunology
Pubmed
Web of science
Create date
09/05/2023 12:59
Last modification date
29/11/2024 16:56
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