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A novel family of human leukocyte antigen class II receptors may have its origin in archaic human species.

ABSTRACT: HLA class II ? and ? chains form receptors for antigen presentation to CD4(+) T cells. Numerous pairings of class II ? and ? subunits from the wide range of haplotypes and isotypes may form, but most of these combinations, in particular those produced by isotype mixing, yielded mismatched dimers. It is unclear how selection of functional receptors is achieved. At the atomic level, it is not known which interactions of class II residues regulate selection of matched ?? heterodimers and the evolutionary origin of matched isotype mixed dimer formation. In this study we investigated assembly of isotype-mixed HLA class II ? and ? heterodimers. Assembly and carbohydrate maturation of various HLA-class II isotype-mixed ? and ? subunits was dependent on the groove binding section of the invariant chain (Ii). By mutation of polymorphic DP? sequences, we identified two motifs, Lys-69 and GGPM-(84-87), that are engaged in Ii-dependent assembly of DP? with DR?. We identified five members of a family of DP? chains containing Lys-69 and GGPM 84-87, which assemble with DR?. The Lys/GGPM motif is present in the DP? sequence of the Neanderthal genome, and this ancient sequence is related to the human allele DPB1*0401. By site-directed mutagenesis, we inspected Neanderthal amino acid residues that differ from the DPB1*0401 allele and aimed to determine whether matched heterodimers are formed by assembly of DP? mutants with DR?. Because the *0401 allele is rare in the sub-Saharan population but frequent in the European population, it may have arisen in modern humans by admixture with Neanderthals in Europe.

SUBMITTER: Temme S

PROVIDER: S-EPMC3887193 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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A novel family of human leukocyte antigen class II receptors may have its origin in archaic human species.

Temme Sebastian S Zacharias Martin M Neumann Jürgen J Wohlfromm Sebastian S König Angelika A Temme Nadine N Springer Sebastian S Trowsdale John J Koch Norbert N

The Journal of biological chemistry 20131108 2

HLA class II α and β chains form receptors for antigen presentation to CD4(+) T cells. Numerous pairings of class II α and β subunits from the wide range of haplotypes and isotypes may form, but most of these combinations, in particular those produced by isotype mixing, yielded mismatched dimers. It is unclear how selection of functional receptors is achieved. At the atomic level, it is not known which interactions of class II residues regulate selection of matched αβ heterodimers and the evolut ...[more]

PMID: 24214983

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Project description:Class II human leukocyte antigens (HLA II) are proteins involved in the human immunological adaptive response by binding and exposing some pre-processed, non-self peptides in the extracellular domain in order to make them recognizable by the CD4+ T lymphocytes. However, the understanding of HLA-peptide binding interaction is a crucial step for designing a peptide-based vaccine because the high rate of polymorphisms in HLA class II molecules creates a big challenge, even though the HLA II proteins can be grouped into supertypes, where members of different class bind a similar pool of peptides. Hence, first we performed the supertype classification of 27 HLA II proteins using their binding affinities and structural-based linear motifs to create a stable group of supertypes. For this purpose, a well-known clustering method was used, and then, a consensus was built to find the stable groups and to show the functional and structural correlation of HLA II proteins. Thus, the overlap of the binding events was measured, confirming a large promiscuity within the HLA II-peptide interactions. Moreover, a very low rate of locus-specific binding events was observed for the HLA-DP genetic locus, suggesting a different binding selectivity of these proteins with respect to HLA-DR and HLA-DQ proteins. Secondly, a predictor based on a support vector machine (SVM) classifier was designed to recognize HLA II-binding peptides. The efficiency of prediction was estimated using precision, recall (sensitivity), specificity, accuracy, F-measure, and area under the ROC curve values of random subsampled dataset in comparison with other supervised classifiers. Also the leave-one-out cross-validation was performed to establish the efficiency of the predictor. The availability of HLA II-peptide interaction dataset, HLA II-binding motifs, high-quality amino acid indices, peptide dataset for SVM training, and MATLAB code of the predictor is available at http://sysbio.icm.edu.pl/HLA .

Project description:BackgroundAssociations between human leukocyte antigens (HLA) alleles and cervical cancer are largely representative of squamous cell carcinoma (SCC), the major histologic subtype. We evaluated the association between HLA class I (A, B, and C) and class II (DRB1 and DQB1) loci and risk of cervical adenocarcinoma (ADC), a less common but aggressive histologic subtype.MethodsWe pooled data from the Eastern and Western US Cervical Cancer studies, and evaluated the association between individual alleles and allele combinations and ADC (n = 630 ADC; n = 775 controls). Risk estimates were calculated for 11 a priori (based on known associations with cervical cancer regardless of histologic type) and 38 non a priori common alleles, as odds ratios (OR) and 95% confidence intervals (CI), adjusted for age and study. In exploratory analysis, we compared the risk associations between subgroups with HPV16 or HPV18 DNA in ADC tumor tissues in the Western US study cases and controls.ResultsThree of the a priori alleles were significantly associated with decreased risk of ADC [DRB1*13:01 (OR = 0.61; 95% CI: 0.41-0.93), DRB1*13:02 (OR = 0.49; 95% CI: 0.31-0.77), and DQB1*06:03 (OR = 0.64; 95% CI: 0.42-0.95)]; one was associated with increased risk [B*07:02 (OR = 1.39; 95% CI: 1.07-1.79)]. Among alleles not previously reported, DQB1*06:04 (OR = 0.46; 95% CI: 0.27-0.78) was associated with decreased risk of ADC and remained significant after correction for multiple comparisons, and C*07:02 (OR = 1.41; 95% CI: 1.09-1.81) was associated with increased risk. We did not observe a difference by histologic subtype. ADC was most strongly associated with increased risk with B*07:02/C*07:02 alleles (OR = 1.33; 95% CI: 1.01-1.76) and decreased risk with DRB1*13:02/DQB1*06:04 (OR = 0.41; 95% CI: 0.21-0.80).ConclusionRESULTS suggest that HLA allele associations with cervical ADC are similar to those for cervical SCC. An intriguing finding was the difference in risk associated with several alleles restricted to HPV16 or HPV18-related tumors, consistent with the hypothesis that HLA recognition is HPV type-specific.

Dataset Information

A novel family of human leukocyte antigen class II receptors may have its origin in archaic human species.

Publications

A novel family of human leukocyte antigen class II receptors may have its origin in archaic human species.

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