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
Institution
Title
Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells.
Journal
Journal of immunology
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
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
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Create date
09/05/2023 12:59
Last modification date
29/11/2024 16:56