Università della Svizzera Italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Bellinzona, Switzerland.
Front Immunol. 2024 Jul 5;15:1426620. doi: 10.3389/fimmu.2024.1426620. eCollection 2024.
The nucleotide-binding and oligomerization domain-like receptors (NLRs) NLR family CARD domain-containing protein 5 (NLRC5) and Class II Major Histocompatibility Complex Transactivator (CIITA) are transcriptional regulators of major histocompatibility complex (MHC) class I and class II genes, respectively. MHC molecules are central players in our immune system, allowing the detection of hazardous 'non-self' antigens and, thus, the recognition and elimination of infected or transformed cells from the organism. Recently, CIITA and NLRC5 have emerged as regulators of selected genes of the butyrophilin () family that interestingly are located in the extended MHC locus. BTNs are transmembrane proteins exhibiting structural similarities to B7 family co-modulatory molecules. The family member BTN2A2, which indeed contributes to the control of T cell activation, was found to be transcriptionally regulated by CIITA. NLRC5 emerged instead as an important regulator of the , , and genes. Together with BTN2A1, BTN3As regulate non-conventional Vγ9Vδ2 T cell responses triggered by selected metabolites of microbial origin or accumulating in hematologic cancer cells. Even if endogenous metabolites conform to the canonical definition of 'self', metabolically abnormal cells can represent a danger for the organism and should be recognized and controlled by immune system cells. Collectively, new data on the role of NLRC5 in the expression of BTN3As link the mechanisms regulating canonical 'non-self' presentation and those marking cells with abnormal metabolic configurations for immune recognition, an evolutionary parallel that we discuss in this perspective review.
核苷酸结合寡聚化结构域样受体（NLRs）NLR 家族含有 CARD 结构域的蛋白 5（NLRC5）和 II 类主要组织相容性复合体转录激活物（CIITA）分别是主要组织相容性复合体（MHC）I 类和 II 类基因的转录调节剂。MHC 分子是我们免疫系统的核心参与者，允许检测危险的“非自身”抗原，从而识别和消除机体中的感染或转化细胞。最近，CIITA 和 NLRC5 已成为某些黏蛋白（BTN）家族基因的调节剂，这些基因有趣的是位于 MHC 基因座的扩展区域。BTNs 是跨膜蛋白，具有与 B7 家族共调节分子相似的结构。家族成员 BTN2A2 确实有助于控制 T 细胞激活，其转录受 CIITA 调控。NLRC5 则成为 、 和 基因的重要调节剂。BTN2A1 和 BTN3As 一起调节由微生物来源的特定代谢物或在血液恶性肿瘤细胞中积累的代谢物触发的非常规 Vγ9Vδ2 T 细胞反应。即使内源性代谢物符合“自身”的典型定义，代谢异常的细胞也可能代表机体的危险，并且应该被免疫系统细胞识别和控制。关于 NLRC5 在 BTN3As 表达中的作用的新数据将调节经典“非自身”呈递的机制与标记具有异常代谢结构的细胞以进行免疫识别的机制联系起来，这是我们在这篇观点综述中讨论的进化平行现象。
