The CD8 coreceptor interaction with the α3 domain of HLA class I is critical to the differentiation of human cytotoxic t-lymphocytes specific for HLA-A2 and HLA-Cw4

Wesley, Pamela K.; Clayberger, Carol; Lyu, Shu cchen; Krensky, Alan M.

doi:10.1016/0198-8859(93)90118-k

Cited by 14 publications

(10 citation statements)

References 23 publications

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“…This confirms that Cw3-wt and Cw3-D227K are expressed at similar high levels on transfected 221 cells and that differences in the cytotoxic response to these transfectants are not a result of inequalities in Cw3 expression levels. As anticipated (62)(63)(64)70), introduction of the D227K mutation into HLA-Cw3 significantly compromised priming of alloreactive CTLs and abrogated CD8-dependent killing of 221 transfectants by anti-Cw3-specific CTLs. Some background killing of 221/Cw3-D227K still occurred, which was similar to that of 221/Cw3-wt in the presence of anti-CD8 mAb blockade.…”

Section: Discussionsupporting

confidence: 54%

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Genetically Modified HLA Class I Molecules Able to Inhibit Human NK Cells Without Provoking Alloreactive CD8+ CTLs

Sharland¹,

Patel²,

Lee³

et al. 2002

The Journal of Immunology

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Human NK cells are likely to be important effectors of xenograft rejection. Expression of HLA class I molecules by transfected porcine cells can protect them from human NK cell-mediated lysis; however, this strategy has the potential to augment the anti-graft response by recipient CD8+ T cells recognizing foreign pig peptides presented by HLA. In this study we show that the introduction of a mutation (D227K) in the α3 domain of HLA-Cw3 abrogates its recognition by CD8-dependent T cells but leaves intact its ability to function as an inhibitory ligand for NK cells. Such genetically modified molecules may have potential therapeutic applications in the prevention of delayed xenograft rejection and in the facilitation of allogeneic and xenogeneic bone marrow engraftment.

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Section: Discussionsupporting

confidence: 54%

“…Therefore, we introduced a well-characterized (62)(63)(64)70) aspartic acid (D) to lysine (K) mutation at position 227 into HLA-Cw3, a group 2 ligand for CD158b. The wild-type (Cw3-wt) and mutant (Cw3-D227K) constructs were expressed in the HLA-A,-B,-C, and -G-negative human NK target cell line LCL 721.221 (221 cells) (71).…”

mentioning

confidence: 99%

Genetically Modified HLA Class I Molecules Able to Inhibit Human NK Cells Without Provoking Alloreactive CD8+ CTLs

Sharland¹,

Patel²,

Lee³

et al. 2002

The Journal of Immunology

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“…This mouse strain also expresses the human CD8a in the form of homodimers on the Tcell membrane for optimal interactions with the a3 domain of the HLA-A(*)02.01 molecule. In fact, several experiments, including crystallographic study, have documented the role of such molecules for correct interactions with human class I HLA molecules (Wesley et al, 1993;Sun et al, 1995;Gao et al, 1997). In this model, such interaction allows murine CTLs to lyse tumour cells of human origin.…”

Section: Discussionmentioning

confidence: 99%

In vivo study of the GC90/IRIV vaccine for immune response and autoimmunity into a novel humanised transgenic mouse

et al. 2003

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Parathyroid hormone-related protein (PTH-rP), a secreted protein produced by prostate carcinoma and other epithelial cancers, is considered a key agent for the development of bone metastases. We investigated the construct GC90/IRIV, composed of immunopotentiating reconstituted influenza virosomes (IRIV) containing PTH-rP gene plasmids (GC90), as a potential tool for human anticancer immunotherapy into humanised mice transgenic for HLA-A(*)02.01, the human-b2 microglobulin, and the human CD8a molecule. Intranasal administration of GC90/IRIV resulted in the induction of a PTH-rP-specific multiepitope cytotoxic T-cell (CTL) response. Cytotoxic T cells derived from vaccinated mice were capable of lysing in vitro syngenic murine PTH-rP transfectants and human HLA-A(*)02.01 þ /PTH-rP þ prostate carcinoma LNCaP cells as well. The immune response capacity and the absence of any sign of toxicity and/or autoimmunity in vivo suggest the GC90/IRIV vaccine as a valid tool for active specific immunotherapy of human cancers and metastases overexpressing PTH-rP. British Journal of Cancer (2003) (Zaccagnini, 1999) and the development of hormone-resistant metastatic bone metastases is one of the major causes of morbidity and mortality related to this malignancy. Parathyroid hormone-related protein (PTH-rP) is an attractive candidate as a target antigen in the protocol of active specific immunotherapy of prostate carcinoma and epithelial malignancy bone metastases. It was originally described as the factor responsible for humoral hypercalcaemia of malignancy (HHM) (Suva et al, 1987;Francini et al, 1993). It is expressed in 90% of prostate and (spindle-cell) lung cell carcinomas and 95% of bone metastases of epithelial cancers, and is produced in small amounts in normal adult tissues (Iguchi et al,

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“…The α3 domain has an important function in maintaining the structure of the HLA molecule and associates with the T‐cell coreceptor, CD8, during T‐cell recognition (39–41). Several clusters of residues in the α3 domain were found to contribute to the CD8 binding site and mutations were found to affect the lysis by CD8‐dependent cytotoxic T‐lymphocytes (CTL) (40, 42, 43). Another crucial role of the α3 domain is its interaction with β2‐microglobulin (44).…”

Section: Discussionmentioning

confidence: 99%

Sequence analysis of exons 1, 2, 3, 4 and 5 of the HLA‐B5/35 cross‐reacting group

2002

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The HLA-B5/35 cross-reacting group (CREG) is a set of closely related antigens including HLA-B35, B51, B52, B53 and B78. The nucleotide sequences of exon 1 through 5 of the B5/35 CREG were determined to assess the level of polymorphism. For exons 2 and 3, the previously described sequence-based typing (SBT) strategy was applied, the nucleotide sequences of exon 1, 4 and 5 were determined by allele-specific sequencing. A total of 225 unrelated individuals were HLA-B typed by heterozygous sequencing of exons 2 and 3. In the B5/35 CREG, 26 different alleles were identified, whereas 63 non-B5/35 CREG alleles were sequenced. The SBT strategy was proven to be reliable and efficient for high resolution typing of the B5/35 CREG. The nucleotide sequences of exon 1, 4 and 5 were determined for the 26 different B5/35 CREG alleles to establish the level of polymorphism. For seven different alleles, of which the exon 1, 4 and 5 sequences were hitherto unknown, the sequences were elucidated and in agreement with the known B5/35 sequences. Nineteen HLA-B5/35 CREG alleles with previously published exon 1, 4 and 5 sequences were sequenced in at least two individuals. Three new alleles were identified. The first, B*5204, showed a difference at position 200 compared to B*52011, which was previously considered a conserved position. The other two alleles, B*3542 and B*51015, showed exon 2 and 3 sequences identical to B*35011 and B*51011, but differences in exons 1 and 4, respectively. B*3542 had differences at position 25 and 72 and B*51015 showed a difference at position 636. More polymorphism might be present outside exons 2 and 3 than previously thought.

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The CD8 coreceptor interaction with the α3 domain of HLA class I is critical to the differentiation of human cytotoxic t-lymphocytes specific for HLA-A2 and HLA-Cw4

Cited by 14 publications

References 23 publications

Genetically Modified HLA Class I Molecules Able to Inhibit Human NK Cells Without Provoking Alloreactive CD8+ CTLs

Genetically Modified HLA Class I Molecules Able to Inhibit Human NK Cells Without Provoking Alloreactive CD8+ CTLs

In vivo study of the GC90/IRIV vaccine for immune response and autoimmunity into a novel humanised transgenic mouse

Sequence analysis of exons 1, 2, 3, 4 and 5 of the HLA‐B5/35 cross‐reacting group

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