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Immunobiology. 2019 May;224(3):388-396. doi: 10.1016/j.imbio.2019.02.009. Epub 2019 Feb 21.

Interferon-γ upregulates Δ42PD1 expression on human monocytes via the PI3K/AKT pathway.

Author information

1
Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.
2
HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.
3
Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: gaozhl@mail.sysu.edu.cn.
4
HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China; AIDS Institute, Research Center for Infection and Immunity, Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China. Electronic address: zchenai@hku.hk.

Abstract

BACKGROUND:

We recently identified a novel alternatively spliced isoform of human programmed cell death 1 (PD-1), named Δ42PD1, which contains a 42-base-pair in-frame deletion compared with the full-length PD-1. Δ42PD1 is likely constitutively expressed on human monocytes and down-regulated in patients infected with human immunodeficiency virus type 1 (HIV-1). The mechanism underlying the regulation of Δ42PD-1 expression in monocytes remains unknown.

METHODS:

By flow cytometry, we investigated the effect of Interferon-gamma (INF-γ) on the expression of Δ42PD1 in primary human monocytes as well as monocytic cell lines THP-1 and U937 cells. In addition, signaling pathway inhibitors and Δ42PD1-specific blocking antibody were used to explore the pathway involved in INF-γ-induced Δ42PD1 upregulation, and to elucidate the relationship between Δ42PD1 and TNF-α or IL-6 production by INF-γ primed monocytes in response to pre-fixed E. coli. Furthermore, we assessed T-cell proliferation, activation and cytokine production as enriched CD4+ T cells were co-cultured with THP-1 or U937 cells, with or without Δ42PD1-blocking antibody.

RESULTS:

Treatment of human peripheral blood mononuclear cells (PBMCs) with IFN-γ resulted in an approximately 4-fold increase in the expression of Δ42PD1 on monocytes. Similarly, IFN-γ upregulates Δ42PD1 expression on human monocytic cell lines THP-1 and U937, in a time- and dose-dependent manner. IFN-γ-induced Δ42PD1 upregulation was abolished by JAK inhibitors Ruxolitinib and Tasocitinib, PI3K inhibitor LY294002, and AKT inhibitor MK-2206, respectively, but not by STAT1 inhibitor and MAPK signaling pathway inhibitors. JAK, PI3K-AKT, and MAPK signaling inhibitors abolished effectively the production of TNF-α and IL-6 in INF-γ-primed monocytes in response to pre-fixed E. coli. In contrast, Δ42PD1-specific blocking antibody did not affect the IFN-γ-induced priming effect. Furthermore, the MFI ratio of Δ42PD1 to full-length PD-1 (PD-1 Δ/F ratio) was significantly and positively correlated with TNF-α (P =  0.0289, r = 0.6038) produced by circulating CD14+ monocytes in response to pre-fixed E. coli. Notably, Δ42PD1 blockage significantly inhibited CD4+ T-cells proliferation and cytokine production in the co-culture conditions.

CONCLUSIONS:

We demonstrated that IFN-γ increases Δ42PD1 expression on human monocytes via activating the PI3K/AKT signaling pathway downstream of JAKs, and that the PD-1 Δ/F ratio is a potential biomarker to predict the functional state of monocytes. Notably, we revealed the Δ42PD1 play a role in T-cell regulation, providing a novel potential approach to manipulate adaptive immune response.

KEYWORDS:

Interferon-γ; JAK/STAT; Monocyte; PD-1; PI3K/AKT; Δ42PD1

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