期刊
JOURNAL OF IMMUNOLOGY
卷 201, 期 3, 页码 971-981出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1701551
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资金
- National Institutes of Health [R01 HL-092565]
- National Institute of Allergy and Infectious Diseases [UM1AI100663, P01AI056299]
- Canadian Institutes for Health Research (CIHR) [137694]
- Canada Foundation for Innovation
- Fonds de Recherche du Quebec Sante (FRQS) AIDS and Infectious Diseases Network
- FRQS Senior Research Scholar Award
- Canada Research Chair Award
- CIHR
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-gamma 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.
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