生物谷报道：在2007年1月出版的《自然—免疫学》中，研究人员描述了一种关键酶的丧失如何实质性地改变了免疫系统对组织抗原的识别。
Nilabh Shastri 和同事仔细研究了一种缺失ERAAP酶的小鼠，看看它是否会出现免疫缺陷。主要组织相容性抗原分子（MHC）是一种组织匹配性抗原，医生会用这种分子来鉴别器官捐赠者与移植患者是否匹配。ERAAP的作用是对由MHC携带到细胞表面的蛋白质进行小小的修饰。本质上讲，这种修饰过程就像将一个超大热狗放入一个小圆面，ERAAP修剪蛋白质中缩氨酸突出的部位，让它舒适地进入MHC分子。
研究显示，当研究人员将缺失ERAAP小鼠的细胞与表达出ERAAP蛋白质的普通型小鼠的细胞混合后，会出现显著的免疫反应。这种免疫反应的程度之强类似于接受MHC不匹配移植患者出现的排斥反应过程。这些结果表明，与普遍型小鼠相比，在缺失ERAAP的细胞中所采集到的蛋白质有很大的不同。作者推测，抑制肿瘤中ERAAP的功能也许能提高它们成为靶标的能力，从而让免疫系统能够消灭它们，或者反过来说，健康组织中ERAAP功能的缺失也可能会导致自体免疫性疾病。
原文出处：
Nature Immunology January 2007, Volume 8 No 1
In the absence of aminopeptidase ERAAP, MHC class I molecules present many unstable and highly immunogenic peptides pp101 - 108
Gianna Elena Hammer, Federico Gonzalez, Edward James, Hector Nolla & Nilabh Shastri
Published online: 26 November 2006 | doi:10.1038/ni1409
Abstract | Full text | PDF (1,920K) | Supplementary Information
See also: News and Views by Delgado & Jensen
作者简介：
Nilabh Shastri
Professor of Immunology
Research Interests
We study mechanisms of immunesurveillance. The immune system detects and eliminates microbial pathogens and cancer cells. Regrettably, the immune system also rejects transplanted tissues and often self-tissues as well. We have identified several antigen genes that uniquely define cancer cells, microbial pathogens, and transplanted tissues as targets for the immune system. We study the molecular mechanisms that generate these antigenic structures and determine their immunogenicity.
Current Projects
The T lymphocytes recognize peptides bound to MHC molecules on the surface of antigen presenting cells (APC). Because the peptides are derived from intracellular proteins the display of these peptide/MHC complexes on the APC surface allows T cells to detect antigens that are sequestered intracellularly and thus, inaccessible to soluble antibody molecules. The antigen processing pathway continuously degrades thousands of intracellular proteins into peptide fragments that are transported to the APC surface by the MHC molecules. When the MHC molecules are found to contain unique peptides derived from viruses, bacteria or mutated genes, the T cells can eliminate the cells bearing these peptide/MHC complexes. The repertoire of peptide/MHC complexes thus defines the immunological identity of cells as perceived by the T cell receptors. The identity and source of these unique peptide/MHC and the antigen processing mechanisms that generate them are poorly understood.
To identify unknown T cell stimulating antigens, we developed the "lacZ" assay for measuring antigen-specific T cell activation in single cells. T-cells harboring the inducible β-galactosidase (lacZ) reporter gene are exquisitely sensitive probes for detecting the peptide/MHC complex displayed on the cell surface. Because the peptide/MHC complexes can be generated via gene transfer into APC, we can screen DNA libraries to isolate the relevant genes that encode the T cell stimulating antigen. This expression cloning strategy has revealed the identity of several T cell stimulating antigens from tumors, pathogenic bacteria and transplanted tissues. Intriguingly, the antigenic peptides are encoded within conventional "open" as well as "non-coding" cryptic translational reading frames and are generated by a novel translational initiation mechanism. Identification of other unique peptides and studies on their role in mediating T cell immunity are underway.
We study the mechanisms of antigen processing by cellular, genetic and biochemical approaches. Cells generate the peptide/MHC complex when they express the gene encoding the antigenic peptide sequence (e.g. viral gene) and the MHC molecule. The naturally processed peptides are identified in cell extracts by high performance liquid chromatography using T cell assays. By manipulating the genes for the antigen, the MHC and other molecules, we have defined key molecular mechanisms for generating antigenic peptides from precursor proteins. We are interested in how cells sample thousands of gene products via this pathway and in the intermediate steps that lead to the final peptide/MHC complex
on the cell surface.
Selected Publications
When peptides don’t make the final cut: Loss of ERAAP aminopeptidase disrupts the peptide repertoire displayed by MHC I. [G.E. Hammer, F. Gonzalez, M. Champsaur, D. Cado and N. Shastri (2005) Nature Immunology (In press)]
All the peptides that fit. The beginning, the middle, and the end of the MHC class I antigen processing pathway. [N. Shastri, S. Cardinaud, S. R. Schwab, T. Serwold and J. Kunisawa (2005) Immunological Reviews (In press)]
Unanticipated antigens: Translational initiation at CUG with a leucine. [S. R. Schwab, J. Shugart, T. Horng, S. Malarkannan, and N. Shastri (2004) PLoS Biology 2:e366]
The Group II chaperonin TriC protects antigenic intermediates from degradation in the MHC class I antigen processing pathway. [J. Kunisawa and N. Shastri (2003) Molecular Cell 12: 565-576]
MHC I molecules constitutively present cryptic translation products. [S. R. Schwab, K. Li, C. Kang and N. Shastri (2003) Science 301, 1367-1371]
Second class minors. Molecular identification of the autosomal H46 histocompatibility locus as a peptide presented by MHC class II molecules. [H. Sahara and N. Shastri (2003) J. Exp. Med.197, 375-385]
ERAAP customizes peptides for presentation by MHC class I molecules in the endoplasmic reticulum. [T. Serwold, F. Gonzalez, J. Kim, R. Jacob and N. Shastri (2002) Nature 419, 480-483]
Producing nature's gene-chips: The generation of peptides for display by MHC class I molecules. [N. Shastri, S. Schwab and T. Serwold (2002) Annual Reviews in Immunology, 20:463-493]
Differences that matter: Major cytotoxic T cell stimulating minor histocompatibility antigens. [S. Malarkannan, T. Horng, P. Eden, F. Gonzalez, P. Shih, N. Brouwenstijn, D. Roopenian and N. Shastri (2000) Immunity 13:333-344]
Last Updated 2005-08-17
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