Expression of hybrid class I genes of the major histocompatibility complex in mouse L cells.

Straus, Daniel S.; Stroynowski, Iwona; Schiffer, Steffen; Hood, Leroy

doi:10.1073/pnas.82.18.6245

Cited by 23 publications

(24 citation statements)

References 24 publications

(48 reference statements)

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“…Chimeric MHC class I genes have been useful in identifying coding sequences for the antigenic determinants recognized by humoral and cellular immune responses (7,(17)(18)(19)(20), analyzing the function of the transmembrane domain (21,22), and defining sequences that control tissue-specific expression (23,24). In past studies, we noted that L cells transfected with TL coding genes expressed low levels of TL antigen, in contrast to high H-2 expression after transfection of H-2 coding genes.…”

Section: Discussionmentioning

confidence: 99%

Influence of 5' flanking sequences on TL and H-2 expression in transfected L cells.

Obata

Stockert²,

Chen³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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TL (thymus leukemia) antigens are encoded by genes in the major histocompatibility complex (MHC) of the mouse. Although similar in overall structure to other class I MHC antigens (H-2, Qa), TL expression is regulated in a highly distinctive fashion. In contrast to the broad distribution of H-2 and the intermediate distribution of Qa, TL expression is restricted to cells of T-cell derivation during development in the thymus and is lost when T cells migrate to the periphery. Some mouse strains do not express TL antigens on thymocytes (TL-strains), but leukemias occurring in these mice can have a TL+ phenotype, indicating activation of normally silent TL genes. In transfection studies with H-2 or TL genes in L cells (mouse fibroblasts), H-2 is expressed at high levels, whereas TL is poorly expressed. To identify genetic elements that regulate expression in transfected L cells, chimeric genes were constructed by transposing the 5' and 3' regions of TL and H-2 genes. Antigen expression was not influenced by transposing the cytoplasmic domain and 3' untranslated region. In contrast, interchanging the 5' flanking sequences and exon 1 had a marked influence on antigen expression, with 5' sequences from the H-2 gene increasing TL expression 10-to 50-fold, and 5' sequences from the TL gene markedly decreasing H-2 expression. With both the parental TL gene (p20-TL) and the highly expressed chimeric TL gene (construct 3), levels of TL mRNA and TL antigen correlated with the number of transfected gene copies. However, in cells transfected with equal copy numbers, much higher levels of TL mRNA and TL antigen were found in construct-3 transfectants than in p20-TL transfectants. In addition, there was marked heterogeneity in TL mRNA size in L cells transfected with p20-TL, in contrast to a more homogeneous transcript size in construct-3 transfectants. These results point to regulatory sequences in the 5' flanking region of class I genes that control proper initiation and processing of TL transcripts.TL antigens of the mouse are cell surface antigens restricted to thymocytes and leukemia cells (1). Three levels of regulation of antigen expression exist: (i) TL+ vs. TL-thymocytes (strain-specific expression); (ii) TL+ vs. TL-T cells (differentiation-specific expression); and (iii) anomalous occurrence of TL+ leukemias in TL-mice (leukemiaspecific expression). To examine the basis for these differences in TL regulation, we and others have cloned and sequenced TL genes from normal and leukemia cells of various mouse strains (2-5). Apparently competent TL genes have been isolated from TL-(non-expressor) strains, and no obvious structural basis has as yet been found to account for strain-specific or leukemia-specific TL expression (1, 2, 4). Both H-2 and TL genes belong to the major histocompatibility complex (MHC) class I family and show clear structural homology, with the major distinction being the number of exons coding for the 3' cytoplasmic domain (one exon in TL genes and three exons in H-2 genes) (2, 4). Although TL ...

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Section: Discussionmentioning

confidence: 99%

Influence of 5' flanking sequences on TL and H-2 expression in transfected L cells.

Obata

Stockert²,

Chen³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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“…The lack of cell surface expression of the polypeptides encoded by the Q genes after transfection of the genes into L cells can be explained by the early translational termina tion codon at the end of the transmembrane exon. Other approaches to the study of Qa-2 region gene expression have involved the transfection of hybrid genes [44][45][46]. The constructs contained exon 1 to 3 of Q genes ligated to the 3' portion (exon 4 to the 3' untranslated region) of an H-2 class I gene.…”

Section: Expression Of the Q Region Genesmentioning

confidence: 99%

Molecular biology of the mouse Q region

Weiß

1987

Immunol Res

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“…These changes result in the loss of GPI-processing, phosphatidylinositolphospholipase C-insensitive surface display and drastically reduced surface expression of the "even" Qa-2 proteins relative to the "odd" Qa-2 (20,21). It has been previously shown that higher expression levels of Q8 can be restored by swapping their 3Ј gene regions with the corresponding exons of the classical class I MHC genes (22). In this model, to enhance the surface display and allow for serological monitoring of the even Qa-2 products in transfected tumors, we substituted exons 4 and 5 of Q8 with exons 4 and 5 of Q9.…”

Section: Tap-dependent Expression Of Q8 On the Surface Of Transfectedmentioning

confidence: 99%

“…To determine whether B78H1 TAP-positive transfectants support expression of Q8 with previously defined serological properties (22,23), transfectants were stained with additional mAbs. Fig.…”

Section: Tap-dependent Expression Of Q8 On the Surface Of Transfectedmentioning

confidence: 99%

The Role of Structurally Conserved Class I MHC in Tumor Rejection: Contribution of the Q8 Locus

Chiang

Stroynowski

2006

The Journal of Immunology

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The mouse multimember family of Qa-2 oligomorphic class I MHC genes is continuously undergoing duplications and deletions that alter the number of the two “prototype” Qa-2 sequences, Q8 and Q9. The frequent recombination events within the Q region lead to strain-specific modulation of the cumulative Qa-2 expression levels. Q9 protects C57BL/6 hosts from multiple disparate tumors and functions as a major CTL restriction element for shared tumor-associated Ags. We have now analyzed functional and structural properties of Q8, a class I MHC that differs significantly from Q9 in the peptide-binding, CTL-interacting α1 and α2 regions. Unexpectedly, we find that the extracellular domains of Q8 and Q9 act similarly during primary and secondary rejection of tumors, are recognized by cross-reactive antitumor CTL, have overlapping peptide-binding motifs, and are both assembled via the transporter associated with the Ag processing pathway. These findings suggest that shared Ag-presenting functions of the “odd” and “even” Qa-2 loci may contribute to the selective pressures shaping the haplotype-dependent quantitative variation of Qa-2 protein expression.

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Expression of hybrid class I genes of the major histocompatibility complex in mouse L cells.

Abstract: The class I genes of the major histocompati-

Cited by 23 publications

References 24 publications

Influence of 5' flanking sequences on TL and H-2 expression in transfected L cells.

Influence of 5' flanking sequences on TL and H-2 expression in transfected L cells.

Molecular biology of the mouse Q region

The Role of Structurally Conserved Class I MHC in Tumor Rejection: Contribution of the Q8 Locus

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