PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

Xu, Xiaozheng; Hou, Bowen; Fulzele, Amit; Masubuchi, Takeya; Zhao, Yunlong; Wu, Zhenru; Hu, Yawen; Jiang, Yong; Ma, Yanzhe; Wang, Haopeng; Bennett, Eric J.; Fu, Guo; Hui, Enfu

doi:10.1083/jcb.201905085

Cited by 73 publications

(93 citation statements)

References 71 publications

(118 reference statements)

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“…As immune checkpoint receptors, BTLA and PD‐1 signaling appear to play independent roles in inhibiting γδ T cell proliferation and cytotoxicity, respectively, and they had no additive effect on each other. In a recent report, BTLA and PD‐1 regulate T cell signaling differentialy and only partially through SHP‐1 and SHP‐2, 44 that supports our study. In Terms of activating signaling, dual inhibition of BTLA and PD‐1 increased pAKT, compared with that of BTLA single blockade, implying the importance of BTLA signaling in γδ T cells.…”

Section: Discussionsupporting

confidence: 91%

The BTLA and PD‐1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells

Hwang

Lee

Kang

et al. 2020

Immunity Inflam & Disease

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Background B‐ and T‐lymphocyte attenuator (BTLA) and programmed cell death‐1 (PD‐1) inhibit γδ T cell homeostasis and activation. This study aimed to determine whether BTLA and PD‐1 signaling pathways were convergent or independent in human peripheral blood γδ T cells. Herein we demonstrate that the signalings of BTLA and PD‐1 regulated proliferation and cytotoxicity of human γδ T cells, respectively. Methods Human peripheral blood γδ T cells were cultured with inactivated Jurkat cells in the presence of interleukin‐2 and zoledronate (Zol) for 14 days. Flow cytometry was performed to evaluate the phenotypes and functions of γδ T cells. Results The proliferation of the γδ T cells was increased when PBMCs were cocultured with inactivated herpes virus entry mediator (HVEM)low Jurkat cells. The cytotoxicity of the expanded γδ T cells was not affected by coculture with inactivated HVEMlow Jurkat cells and was further increased in the presence of anti‐PD‐L1 mAb. These results suggest that the inactivation of the BTLA signaling pathway during expansion could help produce more γδ T cells without compromising γδ T cell function. The inhibition of BTLA or PD‐1 signaling repressed phosphorylation of the src homology region 2‐containing protein tyrosine phosphatase 2 and increased the phosphorylation of protein kinase B in γδ T cells. However, there were no synergistic or additive effects by a combination of BTLA and PD‐1 blockade. Conclusion These results suggest that BTLA signaling is crucial in regulating γδ T cell proliferation and function and that the BTLA and PD‐1 signaling pathways act independently on the proliferation and cytotoxicity of human peripheral γδ T cells.

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Section: Discussionsupporting

confidence: 91%

The BTLA and PD‐1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells

Hwang

Lee

Kang

et al. 2020

Immunity Inflam & Disease

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“…B and T lymphocyte attenuator (BTLA) is selectively expressed on Th1 cells and has been identified as an immune checkpoint receptor. Upon BTLA binding to herpesvirus entry mediator (HVEM), the BTLA cytoplasmic domains ITIM and ITSM bind to and activate the tyrosine phosphatases SHP-1 and SHP-2, which leads to the inhibition of lymphocyte-specific protein tyrosine kinase (LCK)-dependent T-cell activation [39,40]. Additionally, the third domain Grb-2-recognition motif in BTLA can recognize the Grb-2 protein, subsequently recruiting the PI3K protein subunit p85, stimulating the PI3K signaling pathway, and finally promoting cell proliferation and survival.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

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“…Although many in vitro studies indicate the important role of SHP-2 in PD-1-mediated T-cell suppression, recent in vivo study using T cell-specific SHP-2-deficient mice suggests that SHP-2 is dispensable for T-cell exhaustion and for PD-1 signaling [70]. Consistently, another recent research indicates that PD-1 can suppress T-cell signaling by a mechanism independent of both SHP-1 and SHP-2 [71]. These reports suggest that redundant mechanisms other than SHP-1 and SHP-2 may exist to mediate the immune inhibitory function downstream of PD-1.…”

Section: Pd-1/pd-l1-related Cell Signaling and The Control Of Pd-1/pdmentioning

confidence: 93%

A snapshot of the PD-1/PD-L1 pathway

Ghosh¹,

Luong²,

Sun³

2021

J. Cancer

127

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Cancer cells can evade the attack from host immune systems via hijacking the regulatory circuits mediated by immune checkpoints. Therefore, reactivating the antitumor immunity by blockade of immune checkpoints is considered as a promising strategy to treat cancer. Programmed death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) are critical immune checkpoint proteins that responsible for negative regulation of the stability and the integrity of T-cell immune function. Anti-PD-1/PD-L1 drugs have been developed for immune checkpoint blockade and can induce clinical responses across different types of cancers, which provides a new hope to cure cancer. However, the patients' response rates to current anti-PD-1 or anti-PD-L1 therapies are still low and many initial responders finally develop resistance to these therapies. In this review, we provides a snapshot of the PD-1/PD-L1 molecular structure, mechanisms controlling their expression, signaling modulated by PD-1/PD-L1, current anti-PD-1/PD-L1 therapies, and the future perspectives to overcome the resistance.

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PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

Cited by 73 publications

References 71 publications

The BTLA and PD‐1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells

The BTLA and PD‐1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells

Immune Checkpoints in Viral Infections

A snapshot of the PD-1/PD-L1 pathway

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