Sibille C, Gould K G, Willard-Gallo K, Thomson S, Rivett A J, Powis S, Butcher G W, De Baetselier P
Institut de Pathologie et de Génétique de Loverval, Gerpinnes, Belgium.
Curr Biol. 1995 Aug 1;5(8):923-30. doi: 10.1016/s0960-9822(95)00182-5.
Major histocompatibility complex (MHC) class I molecules present short peptides generated by intracellular protein degradation to cytotoxic T lymphocytes (CTL). The multisubunit, non-lysosomal proteinases known as proteasomes have been implicated in the generation of these peptides. Two interferon-gamma (IFN-gamma)-inducible proteasome subunits, LMP2 and LMP7, are encoded within the MHC gene cluster in a region associated with antigen presentation. The incorporation of these LMP subunits into proteasomes may alter their activity so as to favour the generation of peptides able to bind to MHC class I molecules. It has been difficult, however, to demonstrate a specific requirement for LMP2 or LMP7 in the presentation of peptide epitopes to CTL.
We describe a T-cell lymphoma, termed SP3, that displays a novel selective defect in MHC class I-restricted presentation of influenza virus antigens. Of the MHC-encoded genes implicated in the class I pathway, only LMP2 is underexpressed in SP3 cells. Expression of IFN-gamma in transfected SP3 cells simultaneously restores LMP2 expression and antigen presentation to CTL. Expression of antisense-LMP2 mRNA in these IFN-gamma-transfected cells selectively represses antigen recognition and the induction of surface class I MHC expression. Moreover, the expression of this antisense-LMP2 mRNA in L929 fibroblast cells, which constitutively express LMP2 and have no presentation defect, blocks the presentation of the same influenza virus antigens that SP3 cells are defective in presenting.
Our results show that the LMP2 proteasome subunit can directly influence both MHC class I-restricted antigen presentation and class I surface expression.
主要组织相容性复合体（MHC）I类分子将细胞内蛋白质降解产生的短肽呈递给细胞毒性T淋巴细胞（CTL）。被称为蛋白酶体的多亚基非溶酶体蛋白酶参与了这些肽的产生。两种干扰素-γ（IFN-γ）诱导的蛋白酶体亚基LMP2和LMP7在MHC基因簇中与抗原呈递相关的区域编码。这些LMP亚基掺入蛋白酶体可能会改变其活性，从而有利于产生能够与MHC I类分子结合的肽。然而，很难证明在向CTL呈递肽表位时对LMP2或LMP7有特定需求。
我们描述了一种称为SP3的T细胞淋巴瘤，它在MHC I类限制的流感病毒抗原呈递中表现出一种新的选择性缺陷。在I类途径中涉及的MHC编码基因中，只有LMP2在SP3细胞中表达不足。在转染的SP3细胞中表达IFN-γ可同时恢复LMP2表达和向CTL的抗原呈递。在这些IFN-γ转染的细胞中表达反义LMP2 mRNA可选择性抑制抗原识别和表面I类MHC表达的诱导。此外，在组成性表达LMP2且无呈递缺陷的L929成纤维细胞中表达这种反义LMP2 mRNA，可阻断SP3细胞呈递缺陷的相同流感病毒抗原的呈递。
我们的结果表明，LMP2蛋白酶体亚基可直接影响MHC I类限制的抗原呈递和I类表面表达。
