A Mechanistic Model for Predicting Cell Surface Presentation of Competing Peptides by MHC Class I Molecules.

Denise S M Boulanger,Tim Elliott,Peter V Coveney,Neil Dalchau,Ruth C Eccleston,Andrew Phillips

doi:10.3389/fimmu.2018.01538

Abstract

Major histocompatibility complex-I (MHC-I) molecules play a central role in the immune response to viruses and cancers. They present peptides on the surface of affected cells, for recognition by cytotoxic T cells. Determining which peptides are presented, and in what proportion, has profound implications for developing effective, medical treatments. However, our ability to predict peptide presentation levels is currently limited. Existing prediction algorithms focus primarily on the binding affinity of peptides to MHC-I, and do not predict the relative abundance of individual peptides on the surface of antigen-presenting cells in situ which is a critical parameter for determining the strength and specificity of the ensuing immune response. Here, we develop and experimentally verify a mechanistic model for predicting cell-surface presentation of competing peptides. Our approach explicitly models key steps in the processing of intracellular peptides, incorporating both peptide binding affinity and intracellular peptide abundance. We use the resulting model to predict how the peptide repertoire is modified by interferon-γ, an immune modulator well known to enhance expression of antigen processing and presentation proteins.

Highlights

Cellular immunity has a major role in resistance to infection and cancer
This method measures the abundance of peptides presented at the surface of living cells and not, as for quantitative high-throughput methods, the abundance of peptides remaining bound to MHC after biochemical purification of peptide–MHC complex (pMHC) I complexes from cell lysates
We have developed a mathematical model based on known cellular mechanisms which, despite including only three components (MHC, peptide, and tapasin), can predict pMHC surface expression under physiological conditions, given some knowledge of the intracellular abundance of peptides

Summary

Introduction

CD8 T cells play an important part, by recognizing protein fragments (peptides) that are generated within an infected or cancerous cell and presented on the cell surface by class I major histocompatibility complex (MHC-I) molecules. The abundance of infection- or cancer-specific pMHC complexes on the cell surface is a key factor in the development of an efficient T cell response, where high abundance has been associated with an immunodominance phenomenon in which immune responses focus on only a few of the many potential peptides [1, 2]. Other factors influencing the efficiency of the T cell response include the frequency of T cell precursors of a certain specificity [3], and the affinity of the TCR to its multiple target pMHC complexes.

Methods

Results

Conclusion