Polymorphism in the α3 domain of HLA-A molecules affects binding to CD8

Salter, Russell D.; Norment, Anne M.; Chen, Benjamin P.; Clayberger, Carol; Krensky, Alan M.; Littman, Dan R.; Parham, Peter

doi:10.1038/338345a0

Cited by 226 publications

(147 citation statements)

References 23 publications

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“…During T cell target engagement CD8 binds to the membrane proximal ␣3 domain of class I on the opposing cell. A naturally occurring single amino acid polymorphism in HLA-A68 and HLA-B48 abrogates this binding (25)(26)(27). Apparent in the CD8-HLA co-crystal this polymorphism distorts a protruding loop of the ␣3 domain, although the polymorphic residue at position 245 is not directly involved in contact with CD8 (26).…”

Section: Discussionmentioning

confidence: 99%

KIR3DL1 Polymorphisms That Affect NK Cell Inhibition by HLA-Bw4 Ligand

Carr

Pando

Parham

2005

The Journal of Immunology

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196

206

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The killer cell Ig-like receptor (KIR) gene family encodes MHC class I receptors expressed by NK cells and several T cell subpopulations. Factors contributing to human KIR haplotype diversity are differences in gene number, gene content, and allelic polymorphism. Whereas functional and clinical consequences of the first two factors are established, knowledge of the effects of KIR gene polymorphism is limited to special cases in which signaling function is reversed or cell surface expression lost. In this study we use retrovirally transduced human cell lines to show that 3DL1*002 is a stronger inhibitory receptor for HLA-Bw4 ligands than 3DL1*007. Analysis of mutant 3DL1*002 and 3DL1*007 molecules demonstrates that residue 238 in the D2 domain and 320 in the transmembrane region contribute to the difference in receptor strength. Neither position 238 nor 320 is predicted to interact directly with HLA-Bw4 ligand. This study also revealed that KIR3DL1 and LILRB1 both contribute to developing an inhibitory response to HLA-Bw4 ligands.

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Section: Discussionmentioning

confidence: 99%

KIR3DL1 Polymorphisms That Affect NK Cell Inhibition by HLA-Bw4 Ligand

Carr

Pando

Parham

2005

The Journal of Immunology

Self Cite

196

206

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“…The a domain contains two regions that are implicated in binding CD8 molecules, amino acid positions 220-232 and 244-257 in HLA-A2, and the corresponding positions are 216-228 and 241-254 in duck alleles. In mammals, the presence of an alanine at position 245 is essential for CD8 binding and CD8 + T cell interactions (47), and this residue is conserved in ducks. We note the nonconservative substitution of a positively charged arginine or lysine for the negatively charged glutamine at position 226 within the CD8 binding region in several duck alleles.…”

Section: Expressed Alleles Have Features Of Classical Mhc Class I H Cmentioning

confidence: 99%

Extensive Allelic Diversity of MHC Class I in Wild Mallard Ducks

Fleming-Canepa

Jensen

Mesa

et al. 2016

The Journal of Immunology

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MHC class I is critically involved in defense against viruses, and diversity from polygeny and polymorphism contributes to the breadth of the immune response and health of the population. In this article, we examine MHC class I diversity in wild mallard ducks, the natural host and reservoir of influenza A viruses. We previously showed domestic ducks predominantly use UAA, one of five MHC class I genes, but whether biased expression is also true for wild mallards is unknown. Using RT-PCR from blood, we examined expressed MHC class I alleles from 38 wild mallards (Anas platyrhynchos) and identified 61 unique alleles, typically 1 or 2 expressed alleles in each individual. To determine whether expressed alleles correspond to UAA adjacent to TAP2 as in domestic ducks, we cloned and sequenced genomic UAA-TAP2 fragments from all mallards, which matched transcripts recovered and allowed us to assign most alleles as UAA. Allelic differences are primarily located in α1 and α2 domains in the residues known to interact with peptide in mammalian MHC class I, suggesting the diversity is functional. Most UAA alleles have unique residues in the cleft predicting distinct specificity; however, six alleles have an unusual conserved cleft with two cysteine residues. Residues that influence peptide-loading properties and tapasin involvement in chicken are fixed in duck alleles and suggest tapasin independence. Biased expression of one MHC class I gene may make viral escape within an individual easy, but high diversity in the population places continual pressure on the virus in the reservoir species.

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“…A range of experimental approaches reported in 1988-9, including co-immunoprecipitation studies, cell-cell-binding assays, and the use of artificial vesicles expressing purified CD8 or HLA molecules, definitively demonstrated that CD8 is a co-receptor of class I MHC [49][50][51]. The identification of class I MHC alleles with low CD8-binding affinity, coupled with sitedirected mutagenesis, revealed that CD8 binds the a3 domain of class I MHC molecules [52]. Thus, almost 15 years after the discovery that CD8 was associated with the lytic fraction of Thy-1-bearing lymphocytes, it was now not just a marker, but intimately tied to target recognition.…”

Section: The Enlightenmentmentioning

confidence: 99%