PD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow

Yao Yu, Rong-Rong Wang, Nai-Jun Miao, Jia-Jie Tang, Yun-Wei Zhang, Xiang-Ran Lu, Pei-Yi Yan, Jing Wang and Xin-Ming Jia ()
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Yao Yu: Tongji University School of Medicine
Rong-Rong Wang: Tongji University School of Medicine
Nai-Jun Miao: Shanghai JiaoTong University School of Medicine
Jia-Jie Tang: Tongji University School of Medicine
Yun-Wei Zhang: Tongji University School of Medicine
Xiang-Ran Lu: Tongji University School of Medicine
Pei-Yi Yan: Shanghai People’s Hospital of Putuo District
Jing Wang: Shanghai JiaoTong University School of Medicine
Xin-Ming Jia: Tongji University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Programmed death ligand 1 (PD-L1) has been shown to be inducibly expressed on neutrophils to suppress host immunity during polymicrobial sepsis, virus and parasite infections. However, the role of PD-L1 on neutrophil-mediated antifungal immunity remains wholly unknown. Here, we show that the expression of PD-L1 on murine and human neutrophils was upregulated upon the engagement of C-type lectin receptor Dectin-1 with its ligand β-glucans, exposed on fungal pathogen Candida albicans yeast. Moreover, β-glucan stimulation induced PD-L1 translocation into nucleus to regulate the production of chemokines CXCL1 and CXCL2, which control neutrophil mobilization. Importantly, C. albicans infection-induced expression of PD-L1 leads to neutrophil accumulation in bone marrow, through mediating their autocrine secretion of CXCL1/2. Furthermore, neutrophil-specific deficiency of PD-L1 impaired CXCL1/2 secretion, which promoted neutrophil migration from bone marrow into the peripheral circulation, thereby conferring host resistance to C. albicans infection. Finally, either PD-L1 blockade or pharmacological inhibition of PD-L1 expression significantly increased neutrophil release from bone marrow to enhance host antifungal immunity. Our data together indicate that activation of Dectin-1/PD-L1 cascade by β-glucans inhibits neutrophil release from bone marrow reserve, contributing to the negative regulation of antifungal innate immunity, which functions as a potent immunotherapeutic target against life-threatening fungi infections.

Date: 2022
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DOI: 10.1038/s41467-022-34722-7

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