Consiglio Nazionale delle Ricerche, Istituto di Chimica Biomolecolare, Via Campi Flegrei 34, 80078, Pozzuoli, Napoli, Italy.
Bio-Organic Chemistry Unit, Institute of Bio-Molecular Chemistry, National Research Council, Via Campi Flegrei 34, 80078, Pozzuoli, Italy.
Cell Mol Life Sci. 2022 Jun 20;79(7):369. doi: 10.1007/s00018-022-04297-z.
The immune response arises from a fine balance of mechanisms that provide for surveillance, tolerance, and elimination of dangers. Sulfavant A (SULF A) is a sulfolipid with a promising adjuvant activity. Here we studied the mechanism of action of SULF A and addressed the identification of its molecular target in human dendritic cells (hDCs).
Adjuvant effect and immunological response to SULF A were assessed on DCs derived from human donors. In addition to testing various reporter cells, target identification and downstream signalling was supported by a reverse pharmacology approach based on antibody blocking and gene silencing, crosstalk with TLR pathways, use of human allogeneic mixed lymphocyte reaction.
SULF A binds to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2) and initiates an unconventional maturation of hDCs leading to enhanced migration activity and up-regulation of MHC and co-stimulatory molecules without release of conventional cytokines. This response involves the SYK-NFAT axis and is compromised by blockade or gene silencing of TREM2. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and increased interleukin-10 release after lipopolysaccharide stimulation.
SULF A is the first synthetic small molecule that binds to TREM2. The receptor engagement drives differentiation of an unprecedented DC phenotype (homeDCs) that contributes to immune homeostasis without compromising lymphocyte activation and immunogenic response. This mechanism fully supports the adjuvant and immunoregulatory activity of SULF A. We also propose that the biological properties of SULF A can be of interest in various physiopathological mechanisms and therapies involving TREM2.
免疫反应源于一系列精细平衡的机制，这些机制提供了监视、耐受和消除危险的功能。Sulfavant A（SULF A）是一种具有潜在佐剂活性的硫脂。本研究旨在探讨 SULF A 的作用机制，并确定其在人树突状细胞（hDCs）中的分子靶点。
通过来自人类供体的 DC 评估 SULF A 的佐剂效应和免疫反应。除了测试各种报告细胞外，基于抗体阻断和基因沉默、与 TLR 途径的串扰、使用人同种异体混合淋巴细胞反应的反向药理学方法支持了靶标鉴定和下游信号转导。
SULF A 与髓样细胞触发受体 2（TREM2）结合，并启动 hDC 不成熟的成熟，导致迁移活性增强和 MHC 和共刺激分子上调，而无常规细胞因子释放。这种反应涉及 SYK-NFAT 轴，并且通过 TREM2 的阻断或基因沉默而受损。SULF A 的激活保留了 DC 激发同种异体 T 细胞反应的功能，并在脂多糖刺激后增加白细胞介素 10 的释放。
SULF A 是第一个与 TREM2 结合的合成小分子。受体结合驱动了一种前所未有的 DC 表型（homeDCs）的分化，有助于免疫稳态，而不会损害淋巴细胞激活和免疫原性反应。该机制完全支持 SULF A 的佐剂和免疫调节活性。我们还提出，SULF A 的生物学特性可能与涉及 TREM2 的各种生理病理机制和治疗方法有关。
