The Utility of Supertype Clustering in Prediction for Class II MHC-Peptide Binding

Wen-Jun Shen,Xun Zhang,Wenjuan Cui,Cheng Liu,Shaohong Zhang

doi:10.3390/molecules23113034

Abstract

Motivation: Extensive efforts have been devoted to understanding the antigenic peptides binding to MHC class I and II molecules since they play a fundamental role in controlling immune responses and due their involvement in vaccination, transplantation, and autoimmunity. The genes coding for the MHC molecules are highly polymorphic, and it is difficult to build computational models for MHC molecules with few know binders. On the other hand, previous studies demonstrated that some MHC molecules share overlapping peptide binding repertoires and attempted to group them into supertypes. Herein, we present a framework of the utility of supertype clustering to gain more information about the data to improve the prediction accuracy of class II MHC-peptide binding. Results: We developed a new method, called superMHC, for class II MHC-peptide binding prediction, including three MHC isotypes of HLA-DR, HLA-DP, and HLA-DQ, by using supertype clustering in conjunction with RLS regression. The supertypes were identified by using a novel repertoire dissimilarity index to quantify the difference in MHC binding specificities. The superMHC method achieves the state-of-the-art performance and is demonstrated to predict binding affinities to a series of MHC molecules with few binders accurately. These results have implications for understanding receptor-ligand interactions involved in MHC-peptide binding.

Highlights

Major histocompatibility complex (MHC) molecules, called human leukocyte antigen (HLA) in humans, act as cell surface vessels, which hold antigen fragments within their binding groove for recognition by T cells
A large-scale dataset derived from quantitative MHC binding assays was employed to characterize supertypes from the 41 most common class II HLA molecules covering the DR, DP, and DQ loci
We explored the utility of supertype clustering in prediction for class II MHC-peptide binding, including three class II HLA isotypes of HLA-DR, HLA-DP, and HLA-DQ

Summary

Introduction

Major histocompatibility complex (MHC) molecules, called human leukocyte antigen (HLA) in humans, act as cell surface vessels, which hold antigen fragments within their binding groove for recognition by T cells. Class I MHC molecules exist on the surface of most nucleated cells and specialize in displaying antigenic peptides that originate from the cytosol. CD8+ T cells recognize the complex of the class I MHC molecules plus antigenic peptides and kill cells expressing such intracellular antigens. Class II MHC molecules are predominantly expressed on antigen-presenting cells (B cells, macrophages, and dendritic cells) and specialize in displaying antigen fragments that originate from extracellular spaces. CD4+ T cells recognize those foreign peptides in complex with class II MHC molecules and produce a large number of cytokines to activate various cells toward destroying extracellular invaders [3]

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