A Spontaneous H2-Aa Point Mutation Impairs MHC II Synthesis and CD4(+) T-Cell Development in Mice.
A Spontaneous H2-Aa Point Mutation Impairs MHC II Synthesis and CD4(+) T-Cell Development in Mice.
复制标题
DOI：
10.3389/fimmu.2022.810824
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
Shen HH
中科院分区：
文献类型：
--
作者：
Zhao Y;Xiong J;Chen HX;Zhang M;Zhou LN;Wu YF;Li WJ;Fei X;Li F;Zhu C;Li W;Ying SM;Wang L;Chen ZH;Shen HH
主要组织相容性复合物II类（MHC II）是一种重要的免疫调节分子，在抗原呈递和T细胞发育中起重要作用。MHC II表达异常可导致免疫缺陷，临床上称为II型裸淋巴细胞综合征（BLS），其通常由MHC II反式激活因子（CIITA）和其他辅激活因子的突变引起。在这里，我们提出了一个新的模式，在小鼠的MHC II缺乏症，涉及自发点突变H2-Aa。在自噬相关基因微管相关蛋白1轻链3 β（Map 1 lc 3b，Lc 3b）敲除小鼠的长期纯合育种小鼠中观察到CD 4 + T细胞群体显著减少;该表型不归因于原始敲除基因。MHC II的表达普遍减少，连同这些小鼠的免疫细胞中的H2-Aa的显著缺乏。使用cDNA和DNA测序，在这些小鼠中鉴定出自发的H2-Aa点突变，其导致假前mRNA剪接、mRNA中8个碱基的缺失和蛋白质移码。这些发现导致了一种新型的自发性MHCII缺陷的发现，并为解释小鼠II型BLS提供了一种新的范式。
Major histocompatibility complex class II (MHC II) is an essential immune regulatory molecule that plays an important role in antigen presentation and T-cell development. Abnormal MHC II expression can lead to immunodeficiency, clinically termed as type II bare lymphocyte syndrome (BLS), which usually results from mutations in the MHC II transactivator (CIITA) and other coactivators. Here, we present a new paradigm for MHC II deficiency in mice that involves a spontaneous point mutation on H2-Aa. A significantly reduced population of CD4+ T cells was observed in mice obtained from the long-term homozygous breeding of autophagy-related gene microtubule-associated protein 1 light chain 3 β (Map1lc3b, Lc3b) knockout mice; this phenotype was not attributed to the original knocked-out gene. MHC II expression was generally reduced, together with a marked deficiency of H2-Aa in the immune cells of these mice. Using cDNA and DNA sequencing, a spontaneous H2-Aa point mutation that led to false pre-mRNA splicing, deletion of eight bases in the mRNA, and protein frameshift was identified in these mice. These findings led to the discovery of a new type of spontaneous MHC II deficiency and provided a new paradigm to explain type II BLS in mice.