MHC II类分子表达调控的研究进展

MHCII类分子提呈经过加工的抗原给CD4 T淋巴细胞 ,在诱发免疫反应中起重要作用。MHCII类分子不正常表达会引起严重的免疫缺陷疾病 ,如裸淋巴细胞综合征 (BLS)等。目前已识别出四种不同的MHCII调控基因。这些基因分别编码RFXANK、RFX5、RFXAP和CIITA。其中 ,前三个是RFX复合物的亚基 ,RFX是一种结合于所有MHCII类基因启动子上的泛式表达的因子。CIITA是MHCII类分子表达的主要调控因子 ,其严密调控的表达模式决定了MHCII类分子表达的细胞特异性 ,及能否被诱导且在何种水平上表达。本文着重介绍近年来国内外对MHCII类分子表达及其调控研究的新进展     

Interferon Yield and MHC Antigen Expression of Human Medulloblastoma Cells and Its Suppression During Dibutyryl Cyclic AMP-Induced Differentiation: Do Medulloblastoma Cells Derive from Bipotent Neuronal and Glial Progenitors?

1. Human medulloblastoma (ONS-76), a central nervous system (CNS)-derived undifferentiated cell line, was found to possess glial characteristics as defined by responses in the interferon (IFN) system; ONS-76 cells produced as much IFN- as human fibroblast and glioma cells by viral infection and poly(I):poly(C) induction.2. Major histocompatibility complex (MHC) class I antigens were also induced under IFN- stimulation. ONS-76 cells expressed neurofilament protein, as shown by Northern blot analysis, and morphological differentiation was induced by dibutyryl cyclic AMP (dcAMP).3. Expression of IFN- and MHC class I antigens was suppressed in ONS-76 cells during the dcAMP-induced differentiation.4. These results showed that ONS-76 cells possessed a glial properly in IFN system responses and a neuronal property in cytoskeleton protein, suggesting that the precursors of medulloblastoma may be characterized as bipotent neuronal and glial progenitors in CNS.     

Two novel mutations in the MHC class II transactivator CIITA in a second patient from MHC class II deficiency complementation group A

Congenital MHC class II deficiency or bare lymphocyte syndrome (BLS; McKusick 209920) is caused by defects in trans-acting regulatory factors that control MHC class II expression and is therefore a disease of gene regulation. There are at least four complementation groups and the genetic and molecular dissection of this rare disease has contributed considerably to our current understanding of the molecular mechanisms governing MHC class II expression. Identification of the gene that is defective in BLS complementation group A, CIITA (MHC class II transactivator), has led to the discovery that CIITA acts as a master control factor of MHC class II expression. We have identified the CIITA mutations in a second patient from BLS group A. Two novel mutations abolish CIITA function, as shown by transfection experiments. Molecular analysis of these two novel mutations, together with the one described earlier in the first patient, is informative in terms of CIITA structure-function relationships. Received: 19 October 1996 / Revised: 25 November 1996     

MHC class II and CD80 tumor cell–based vaccines are potent activators of type 1 CD4<Superscript>+</Superscript> T lymphocytes provided they do not coexpress invariant chain

We are developing vaccines that activate tumor-specific CD4⁺ T cells. The cell-based vaccines consist of MHC class I⁺ tumor cells that are genetically modified to express syngeneic MHC class II and costimulatory molecules. Previous studies demonstrated that treatment of mice with established tumors with these vaccines resulted in regression of solid tumors, reduction of metastatic disease, and increased survival time. Optimal vaccines will prime naïve T cells and activate T cells to tumor peptides derived from diverse subcellular compartments, since potential tumor antigens may reside in unique cellular locales. To determine if the MHC class II / costimulatory molecule vaccines fulfill these conditions, the vaccines have been tested for their ability to activate antigen-specific, naïve, transgenic CD4⁺ T lymphocytes. MHC class II⁺CD80⁺ vaccine cells were transfected with hen eggwhite lysozyme targeted to the cytosol, nuclei, mitochondria, or endoplasmic reticulum, and used as antigen-presenting cells to activate I-A^k–restricted, lysozyme-specific CD4⁺ 3A9 transgenic T cells. Regardless of the cellular location of lysozyme, the vaccines stimulated release of high levels of IFN- and IL-2. If the vaccines coexpressed the MHC class II accessory molecule invariant chain, then IFN- and IL-2 release was significantly reduced. These studies demonstrate that in the absence of invariant chain the MHC class II and CD80 tumor cell vaccines (1) function as antigen-presenting cells to activate naïve, tumor-specific CD4⁺ cells to endogenously synthesized tumor antigens; (2) polarize the activated CD4⁺ T cells toward a type 1 response; and (3) present epitopes derived from varied subcellular locales.Abbreviations APC antigen-presenting cells - CIITA MHC class II transactivator - CytoHEL HEL targeted to cytoplasm - ER endoplasmic reticulum - ErHEL HEL targeted to ER - HEL hen eggwhite lysozyme - 3A9 HEL_46–61–specific, I-A^k–restricted TCR - Hph hygromycin - Ii invariant chain - MAb monoclonal antibody - MitoHEL HEL targeted to mitochondria - NucHEL HEL targeted to nucleus - Puro puromycin - TG transgenic - Zeo Zeocin