HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange

Liusong Yin,Lawrence J Stern

doi:10.3389/fimmu.2013.00336

Abstract

Peptides presented by major histocompatibility complex class II (MHCII) molecules to CD4+ T cells play a central role in the initiation of adaptive immunity. This antigen presentation process is characterized by the proteolytic cleavage of foreign and self proteins, and loading of the resultant peptides onto MHCII molecules. Loading and exchange of antigenic peptides is catalyzed by a non-classical MHCII molecule, HLA-DM. The impact of HLA-DM on epitope selection has been appreciated for a long time. However, the molecular mechanism by which HLA-DM mediates peptide exchange remains elusive. Here, we review recent efforts in elucidating how HLA-DM works, highlighted by two recently solved co-structures of HLA-DM bound to HLA-DO (a natural inhibitor of HLA-DM), or to HLA-DR1 (a common MHCII). In light of these efforts, a model for HLA-DM action in which HLA-DM utilizes conformational flexibility around the P1 pocket of the MHCII-peptide complex to catalyze peptide exchange is proposed.

Highlights

Major histocompatibility complex class II (MHCII) proteins are expressed constitutively on the surface of professional antigenpresenting cells, and induced by inflammatory stimuli on many other cell types
It has been found that HLA-DM extinguishes the presentation of cryptic epitopes and stimulates the presentation of immunodominant epitopes [10], and that the effects of HLA-DM editing can be altered by manipulation of the kinetic stability of MHCII-peptide complexes [11]
We and others have demonstrated that the kinetic stability of MHCII-peptide complexes in the presence of HLA-DM directly correlates with immunogenicity [12,13,14]

Summary

INTRODUCTION

Major histocompatibility complex class II (MHCII) proteins are expressed constitutively on the surface of professional antigenpresenting cells, and induced by inflammatory stimuli on many other cell types. Some immunodominant epitopes are found to have low affinities and low kinetic stabilities; notably most derive from self-antigens and are often associated in autoimmune diseases [15,16,17,18] In these cases, it is possible that self-peptides bound to MHCII alleles escaped HLA-DM editing due to downregulation, inhibition, or deficiency of HLA-DM in antigen presenting cells. The ability of HLA-DM to catalyze the exchange of a wide variety of peptides implicated the hydrogen bond network as an ideal target for HLA-DM [22] This idea was experimentally demonstrated in several studies, which in general highlighted a role for MHCII-peptide hydrogen bonds near P1 pocket [23,24,25]. A seeming discrepancy came from two subsequent studies demonstrating that HLA-DM functions normally on MHCII-peptide complexes lacking conserved side-chain hydrogen bonds [26, 27], but it is important to note that neither study looked at the contribution of MHC main chain hydrogen bonds as described in Stratikos et al these studies suggested that individual hydrogen bonds may not be the key target www.frontiersin.org

Yin and Stern

CONCLUSION