A framework to sub-type HLA supertypes

Abstract

The human leukocyte antigen (HLA) alleles are extremely polymorphic among ethnic population and the peptide binding specificity varies for different alleles in a combinatorial manner. However, it has been suggested that majority of alleles can be covered within few HLA supertypes, where different members of a supertype bind similar peptides, yet exhibiting distinct repertoires. Since the overlap between different members of a supertype appears to be extensive, it is crucial to develop a framework for grouping alleles into supertypes just from sequence information. In this report, we define sub supertypes, where members show functional overlap with identical repertoire, and describe a strategy to group HLA-A, B and C alleles into different categories of sub supertypes. The strategy grouped 47% of 295 A alleles, 44% of 540 B alleles and 35% of 156 C alleles to just 36, 71 and 18 groups, respectively. The grouping is moderately validated using available binding data. However, the validation is limited due to lack of binding data. Hence, the data presented in this article serve as a framework to test specific functional overlap between alleles. The grouping of HLA alleles into different categories of sub supertypes has profound use in the understanding of antigenic peptide selection, degeneration and discrimination during T-cell mediated immune response. A complete knowledge of this phenomenon finds utility in epitope design for the development of HLA based vaccines and immuno-therapeutics.

Cross-Species Dependence of Ly49 Recognition on the Supertype Defining B-Pocket of a Class I MHC Molecule

“…The equal distribution of supertypes across species (20,21) and even human ethnicities, although allele representation within those supertypes varies (48), implies that a certain complement of supertypes is required within a population to provide immune fitness toward a battery of pathogens (49). Because there are no MHC I orthologs between rat and mouse or between rodents and humans (50), and because examination of the B-pocket structure of murine vs primate supertypes shows a large difference in the pocket structures, it appears that convergent evolution has occurred to produce similar supertypes in both mammalian orders.…”

Prediction of MHC-Peptide Binding: A Systematic and Comprehensive Overview

“…In contrast, Doytchinova et al [102][103][104] have reported a system to classify into supertypes all HLA I and HLA II allelic variants, which is solely based on the 3D structure of MHC molecules. Similarly, Kangueane et al [105] recognized that all HLA-A, -B, and -C alleles can be grouped into supertypes on the basis of several critical polymorphic residues.…”

A comprehensive analysis of predicted HLA binding peptides of JE viral proteins specific to north Indian isolates

“…As discussed earlier, the concept of HLA supertype has a profound role in the understanding of T cell epitope selection, degeneration and discrimination during T cell mediated immune response [30]. In the HLA supertype analysis, IEDB web server was also used to check binding of best epitopes with also those HLA alleles, which are not included in propred server.…”

“…It has been reported that the majority of alleles can be covered within few HLA supertypes, where different members of a supertype bind similar peptides; these similar peptides are called super antigens. Recently, nine major HLA class I supertypes (HLA- HLA- A1, A2, A3, A24, B7, B27, B44, B58, and B62 and seven HLA class II supertypes (main DR, DR4, DRB3, main DQ, DQ7, main DP, and DP2) have been determined by comparing peptide-binding data [30, 31]. Peptides exhibiting super antigenic property by binding to a maximum number of HLA alleles or HLA supertypes with their conserved nature can surmount the problem of HLA allele׳s population coverage and chance of antigen escape related to antigenic drift or shift.…”