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

TitleImmune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells.
Publication TypeJournal Article
Year of Publication2018
AuthorsPorichis F, Hart MG, Massa A, Everett HL, Morou A, Richard J, Brassard N, Veillette M, Hassan M, Le Ly N, Routy J-P, Freeman GJ, Dubé M, Finzi A, Kaufmann DE
JournalJ Immunol
Date Published08/01/2018

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.

Alternate JournalJ Immunol
PubMed ID29934472
PubMed Central IDPMC6064609
Grant ListP01 AI056299 / AI / NIAID NIH HHS / United States
R01 HL092565 / HL / NHLBI NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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