MHC Class II Presentation Is Affected by Polymorphism in the H2-Ob Gene and Additional Loci.
MHC Class II Presentation Is Affected by Polymorphism in the H2-Ob Gene and Additional Loci.
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DOI：
10.4049/jimmunol.2100061
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Golovkina T
中科院分区：
文献类型：
--
作者：
Cullum E;Graves AM;Tarakanova VL;Denzin LK;Golovkina T
病原体来源的多肽被装载在主要组织相容性II类(MHCII)上，并呈递给CD4+T细胞进行激活。MHCII的多肽负载量发生在特殊的内体隔室，并受非经典的MHCII分子H2-M和H2-O控制，这两个分子都是构成αβ的异源二聚体。H2-M催化MHCII肽的负载，而H2-O通过作为MHCII模拟物来调节H2-M的活性。最近，我们发现具有逆转录病毒抗性的I/LnJ小鼠遗传的H2-Ob等位基因导致了不起作用的H2-O。I/LnJ H2-O与H2-M结合，但不抑制H2-M。与病毒敏感小鼠的H2-Oβ相比，I/LnJ小鼠的H2-Oβ有4个独特的氨基酸(AA)替换：3个在免疫球蛋白(Ig)区域，1个在细胞质尾部。在这里，我们证明了I/LnJOβIg结构域上的三个氨基酸对H2-M的H2-O抑制活性是关键的。出乎意料的是，我们发现MHCII在抗原提呈细胞中的呈递方式与两个关系密切的小鼠品系B6J和B6N显著不同，这两个品系携带相同的MHCII、H2-O和H2-M等位基因。利用定位克隆的方法，我们已经确定了B6J和B6N之间的两个多态基因座，它们调节了MHCII呈现的差异。总的来说，这些研究揭示了MHCII/H2-M/H-2O相互作用的额外复杂性，可能涉及尚未确定的途径调节器。
Pathogen-derived peptides are loaded on Major Histocompatibility Class II (MHCII) and presented to CD4+ T cells for their activation. Peptide loading of MHCII occurs in specialized endosomal compartments and is controlled by the non-classical MHCII molecules H2-M and H2-O, which are both constitutive αβ heterodimers. H2-M catalyzes MHCII peptide loading, whereas H2-O modulates H2-M activity by acting as an MHCII mimic. Recently, we discovered that the H2-Ob allele inherited by retrovirus-resistant I/LnJ mice results in nonfunctional H2-O. I/LnJ H2-O binds to but does not inhibit H2-M. Compared to H2-Oβ from virus-susceptible mice, H2-Oβ from I/LnJ mice has 4 unique amino acid (AA) substitutions: three in the immunoglobulin (Ig) domain and one in the cytoplasmic tail. Here we show that the three AAs in the Ig domain of I/LnJ Oβ are critical for the H2-O inhibitory activity of H2-M. Unexpectedly, we found that MHCII presentation was significantly different in antigen presenting cells from two closely related mouse strains, B6J and B6N, which carry identical alleles of MHCII, H2-O, and H2-M. Using a positional cloning approach, we have identified two loci, polymorphic between B6J and B6N, that mediate the difference in MHCII presentation. Collectively these studies reveal extra complexity in MHCII/H2-M/H-2O interactions that likely involve yet to be identified modulators of the pathway.
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