Layet C, Germain R N
Lymphocyte Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2346-50. doi: 10.1073/pnas.88.6.2346.
Invariant chain (Ii) is a nonpolymorphic, non-major histocompatibility complex (MHC)-encoded glycoprotein that rapidly associates with newly synthesized class II MHC alpha and beta chains in the rough endoplasmic reticulum. This oligomerization of Ii, alpha, and beta and their cotransport within the cell led to speculation that Ii was an essential alpha beta transport protein. However, direct tests failed to show an absolute requirement for Ii in class II MHC molecule transport. More recently, it has become clear that different class II alpha beta chain combinations vary greatly in their efficiency of cell-surface expression, based largely on the allelic origin of the alpha and beta amino-terminal regions. Because the previous tests of Ii for a role in class II molecule expression utilized efficiently expressed alpha beta combinations, we have reexamined this question with several haplotype-mismatched murine A alpha and A beta chain combinations of various potentials for cell-surface expression. Using a transient expression assay in Ii-negative COS cells, we find that many inefficiently expressed alpha beta combinations show marked augmentation of surface expression upon cosynthesis of Ii. This effect is absent or minimal with evolutionarily coselected, haplotype-matched chains that give efficient expression alone. Biochemical studies show that at least one component of the Ii effect is an increased egress of already formed alpha beta dimers from the rough endoplasmic reticulum/cis-Golgi. We suggest that these results reflect the interaction of Ii with the peptide-binding domain of the poorly expressed class II molecules, either aiding in maintenance of a transportable conformation or competing with endoplasmic reticulum retention proteins, and thus enhancing movement to the cell surface. These results suggest a complex and variable role for trans-associated alpha and beta chains in the immune responses of MHC heterozygotes and provide a method for examining Ii interaction with class II MHC molecules independent of measurement of peptide presentation to T cells.
恒定链（Ii）是一种非多态性、非主要组织相容性复合体（MHC）编码的糖蛋白，它在粗面内质网中与新合成的II类MHCα链和β链迅速结合。Ii、α链和β链的这种寡聚化以及它们在细胞内的共转运引发了一种推测，即Ii是一种必需的αβ转运蛋白。然而，直接测试未能表明Ii在II类MHC分子转运中是绝对必需的。最近，已经清楚的是，不同的II类αβ链组合在细胞表面表达效率上有很大差异，这在很大程度上基于α链和β链氨基末端区域的等位基因起源。由于之前对Ii在II类分子表达中作用的测试使用的是高效表达的αβ组合，我们用几种细胞表面表达潜力各异的单倍型不匹配的小鼠Aα链和Aβ链组合重新审视了这个问题。通过在Ii阴性的COS细胞中进行瞬时表达分析，我们发现许多低效表达的αβ组合在与Ii共合成时表面表达有显著增强。对于单独就能高效表达的、在进化上共同选择的单倍型匹配链，这种效应不存在或很微小。生化研究表明，Ii效应的至少一个组成部分是已形成的αβ二聚体从粗面内质网/顺式高尔基体的流出增加。我们认为这些结果反映了Ii与低表达的II类分子的肽结合结构域的相互作用，要么有助于维持可转运的构象，要么与内质网保留蛋白竞争，从而增强向细胞表面的移动。这些结果表明反式相关的α链和β链在MHC杂合子的免疫反应中具有复杂且可变的作用，并提供了一种独立于测量向T细胞呈递肽来研究Ii与II类MHC分子相互作用的方法。
