Cutting Edge: PDGF-DD Binding to NKp44 Costimulates TLR9 Signaling and Proinflammatory Cytokine Secretion in Human Plasmacytoid Dendritic Cells

The Journal of Immunology Pub Date : 2023-12-20 DOI:10.4049/jimmunol.2200496

Alexander David Barrow, Marina Cella, Melissa Anne Edeling, Md. Abdullah-Al-Kamran Khan, Luisa Cervantes-Barragan, Mattia Bugatti, Christian Schmedt, William Vermi, Marco Colonna

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Abstract NKp44 is a human receptor originally found on activated NK cells, group 1 and group 3 innate lymphoid cells that binds dimers of platelet-derived growth factor D (PDGF-DD). NKp44 is also expressed on tissue plasmacytoid dendritic cells (PDCs), but NKp44-PDGF-DD interaction on PDCs remains unstudied. Engagement of NKp44 with PDGF-DD in vitro enhanced PDC secretion of IFN-α, TNF, and IL-6 in response to the TLR9 ligand CpG-ODN, but not TLR7/8 ligands. In tissues, PDCs were found in close contact with PDGF-DD–expressing cells in the high endothelial venules and epithelium of tonsils, melanomas, and skin lesions infected with Molluscum contagiosum. Recombinant PDGF-DD enhanced the serum IFN-α response to systemic HSV-1 infection in a humanized mouse model. We conclude that NKp44 integrates with TLR9 signaling to enhance PDC cytokine production. These findings may have bearings for immune responses to TLR9-based adjuvants, therapy for tumors expressing PDGF-DD, and infections with DNA viruses that induce PDGF-DD expression to enhance viral spread.

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前沿：PDGF-DD 与 NKp44 的结合会刺激 TLR9 信号和人类浆细胞状树突状细胞分泌促炎细胞因子

摘要 NKp44 是一种人类受体，最初存在于活化的 NK 细胞、第 1 组和第 3 组先天性淋巴细胞上，能与血小板衍生生长因子 D（PDGF-DD）的二聚体结合。NKp44 也在组织浆细胞树突状细胞（PDCs）上表达，但 PDCs 上的 NKp44-PDGF-DD 相互作用仍未得到研究。在体外，NKp44 与 PDGF-DD 相互作用可增强 PDC 对 TLR9 配体 CpG-ODN 而非 TLR7/8 配体分泌的 IFN-α、TNF 和 IL-6 的反应。在组织中，发现 PDCs 与扁桃体、黑色素瘤和传染性软疣感染的皮肤病变的高内皮静脉和上皮细胞中的 PDGF-DD 表达细胞密切接触。在人源化小鼠模型中，重组 PDGF-DD 增强了血清 IFN-α 对全身 HSV-1 感染的反应。我们的结论是，NKp44 与 TLR9 信号结合，可增强 PDC 细胞因子的产生。这些发现可能会对基于 TLR9 的佐剂的免疫反应、表达 PDGF-DD 的肿瘤治疗以及诱导 PDGF-DD 表达以增强病毒传播的 DNA 病毒感染产生影响。

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The Journal of Immunology

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