Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

doi:10.1016/j.coi.2007.10.007

Current Opinion in Immunology

Volume 20, Issue 1, February 2008, Pages 105-110

https://doi.org/10.1016/j.coi.2007.10.007 Get rights and content

One seminal aspect in autoimmune diabetes is antigen presentation of beta cell antigens by the diabetes-propensity class II histocompatibility molecules. The binding properties of I-A^g7 molecules are reviewed here and an emphasis is placed on their selection of peptides with a highly specific sequence motif, in which one or more acidic amino acids are found at the carboxy end interacting at the P9 anchoring site of I-A^g7. The reasons for the central role of I-A^g7 in the autoimmune response are analyzed. The insulin B chain segment 9–23 is a hot spot for T cell selection and a striking example of a weak MHC binding peptide that triggers autoreactivity.

Introduction

The direct association of major histocompatibility complex (MHC) molecules in the onset of various autoimmune disorders, including type 1 diabetes mellitus (T1DM), points a central role to their peptide-binding features. Several attempts have been made to identify the natural peptides bound to MHC molecules, starting from the pioneering studies of Rammensee [1, 2, 3], and continuing with the introduction of mass spectrometry [4, 5]. In our own experience, we have evaluated naturally processed peptides selected by various murine (I-A^k, I-A^d, I-E^k, I-E^p, I-A^g7, l-A^g7PD and K^d) and human (DQ8) MHC molecules. A conclusion from the identification of large numbers of natural peptides is that each MHC molecule selects for a unique repertoire of peptides in an allele-specific manner.

Section snippets

Biochemical, structural and functional properties of diabetes-associated class II MHC molecules

A notable feature shared between the murine (I-A^g7) and human (DQ2 or DQ8) diabetogenic class II MHC molecules is the expression of a non-Asp amino acid at position 57 of the β chain [6]; most other class II MHC molecules contain a conserved Asp at β57, which forms an ion-pair with an opposing Arg at α76 that defines the rim and the structural features of the P9 pocket of the binding groove [7, 8]. The absence of this salt bridge in the case of diabetogenic class II MHC molecules generated a P9

Weak MHC binding peptides and autoreactivity: the case of the dominant insulin T cell epitope

Insulin, and particularly the 9–23 peptide of the insulin beta chain, is a primary target of T cell reactivity in both the human disease and the NOD mouse [38••, 39•] (in this issue, contribution by Eisenbarth). Initial binding studies of the B:(9–23) peptide to soluble I-A^g7 in detergent free conditions revealed poor binding and fast dissociation rates [10, 13, 14, 40]. The IC₅₀ values for the B:(9–23) peptide were measured in the 5–10 μM range at endosomal pH and the half-life of the complexes

Concluding remarks

An understanding of the biochemical basis of peptides selected by diabetogenic class II MHC molecules is key to gaining insights into the identity and nature of islet β cell antigens that are targeted in diabetes. Analysis of natural peptides has provided useful information with regards to the sequence specificity that can now be applied to predictive algorithms. However, further work needs to clarify the role of the highly specific binding motif of I-A^g7 peptides and thymic selection of the T

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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The proinflammatory effects of macrophage-derived NADPH oxidase function in autoimmune diabetes
2018, Free Radical Biology and Medicine
Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic β-cells. While ultimately a T cell-mediated disease, macrophages play an indispensable role in disease initiation and progression. Infiltrating macrophages generate an inflammatory environment by releasing NADPH oxidase-derived superoxide and proinflammatory cytokines. The synthesis of reactive oxygen species (ROS) is acknowledged as putative factors contributing to autoimmunity and β-cell damage in T1D. In addition to direct lysis, free radicals collectively participate in β-cell destruction by providing a redox-dependent third signal necessary for islet-reactive CD4 and CD8 T cell maturation and by inducing oxidative post-translational modifications of β-cell epitopes to further exacerbate autoimmune responses. This review will provide an overview of macrophage function and a synergistic cross-talk with redox biology that contributes to autoimmune dysregulation in T1D.
Peptide linkage to the α-subunit of MHCII creates a stably inverted antigen presentation complex
2012, Journal of Molecular Biology
Class II proteins of the major histocompatibility complex (MHCII) typically present exogenous antigenic peptides to cognate T cell receptors of CD4-T lymphocytes. The exact conformation of peptide–MHCII complexes (pMHCII) can vary depending on the length, register and orientation of the bound peptide. We have recently found the self-peptide CLIP (class‐II-associated invariant chain‐derived peptide) to adopt a dynamic bidirectional binding mode with regard to the human MHCII HLA-DR1 (HLA, human leukocyte antigen). We suggested that inversely bound peptides could activate specific T cell clones in the context of autoimmunity. As a first step to prove this hypothesis, pMHC complexes restricted to either the canonical or the inverted peptide orientation have to be constructed. Here, we show that genetically encoded linkage of CLIP and two other antigenic peptides to the HLA-DR1 α-chain results in stable complexes with inversely bound ligands. Two‐dimensional NMR and biophysical analyses indicate that the CLIP-bound pMHC^inv complex (pMHC^inv, inverted MHCII–peptide complex) displays high thermodynamic stability but still allows for the exchange against higher‐affinity viral antigen. Complemented by comparable data on a corresponding β-chain-fused canonical HLA-DR1/CLIP complex, we further show that linkage of CLIP leads to a binding mode exactly the same as that of the corresponding unlinked constructs. We suggest that our approach constitutes a general strategy to create pMHC^inv complexes. Such engineering is needed to create orientation-specific antibodies and raise T cells to study phenomena of autoimmunity caused by isomeric pMHCs.
CD4 T cells and their antigens in the pathogenesis of autoimmune diabetes
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Citation Excerpt :
Insulin and IAPP are proteins originating in beta cells, but ChgA is found in secretory granules of other tissues besides the pancreatic islet and may therefore be less obvious as a candidate autoantigen. One hypothesis for the autoantigenic activity of certain ligands in T1D is that these peptides bind to the predisposing MHC class II in an unusual manner, a mechanism that has precedent in other autoimmune disorders such as EAE [51,52], and is exemplified by the ability of insulin B:9-23 to bind to IAg7 in various binding registers [39,40]. The WE14 peptide from ChgA is also a weak binder to IAg7, filling only part of the class II groove [41••].
Pathogenesis of type 1 diabetes (T1D) is mediated by effector T cells and CD4 Th1 and Th17T cells have important roles in this process. While effector function of Th1 cells is well established, because of their inherent plasticity Th17 cells have been more controversial. Th17 cells contribute to pathogenicity, but several studies indicate that Th17 cells transfer disease through conversion to Th1 cells in vivo. CD4T cells are attracted to islets by β-cell antigens which include insulin and the two new autoantigens, chromogranin A and islet amyloid polypeptide, all proteins of the secretory granule. Peptides of insulin and ChgA bind to the NOD class II molecule in an unconventional manner and since autoantigenic peptides may typically bind to MHC with low affinity, it is postulated that post-translational modifications of β-cell peptides could contribute to the interaction between peptides, MHC, and the autoreactive TCR.
Administration of a determinant of preproinsulin can induce regulatory T cells and suppress anti-islet autoimmunity in NOD mice
2010, Clinical Immunology
Antigen-specific immunotherapy is expected to be an ideal strategy for treating type 1 diabetes (T1D). We investigated the therapeutic efficacy of a peptide in the leader sequence of preproinsulin, which was selected because of its binding affinity to the MHC I-A^g7 molecule. Preproinsulin-1 L7–24 peptide (L7–24) emulsified in Freund's incomplete adjuvant was administered subcutaneously to NOD mice. Administration of L7–24 increased the proportion of regulatory T cells in the spleen. Splenocytes of NOD mice immunized with this peptide secreted IL-4 and IL-10 in response to L7–24. This peptide also significantly prevented the development of diabetes and cured some newly diabetic NOD mice without recurrence. L7–24 peptide, which has a high affinity for pockets of I-A^g7, induced regulatory T cells and showed therapeutic effects. This peptide may provide a new approach for developing antigen-specific immunotherapy for autoimmune diabetes.
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View full text

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Introduction

Section snippets

Biochemical, structural and functional properties of diabetes-associated class II MHC molecules

Weak MHC binding peptides and autoreactivity: the case of the dominant insulin T cell epitope

Concluding remarks

References and recommended reading

Immunity

Immunity

Immunity

J Immunol

Cellular peptide composition governed by major histocompatibility complex class I molecules

Nature

Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules

Nature

Pool sequencing of natural HLA-DR, DQ, and DP ligands reveals detailed peptide motifs, constraints of processing, and general rules

Immunogenetics

Self-peptides bound to the type I diabetes associated class II MHC molecules HLA-DQ1 and HLA-DQ8

Int lmmunol

Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad

Science

HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus

Nature

A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes

Science

Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes

Nat Immunol

The motif for peptide binding to the insulin-dependent diabetes mellitus-associated class II MHC molecule I-Ag7 validated by phage display library

Int Immunol

pH-dependent peptide binding properties of the type I diabetes- associated I-Ag7 molecule: rapid release of CLIP at an endosomal pH

J Exp Med

The I-Ag7 MHC class II molecule linked to murine diabetes is a promiscuous peptide binder

J Immunol

Nonobese diabetic mice display elevated levels of class ll-associated invariant chain peptide associated with I-Ag7 on the cell surface

J Immunol

The class II MHC I-Ag7 molecules from non-obese diabetic mice are poor peptide binders

J Immunol

Peptide analysis, stability studies, and structural modeling explain contradictory peptide motifs and unique properties of the NOD mouse MHC class II molecule H2-A(g7)

Eur J Immunol

The inability of the nonobese diabetic class II molecule to form stable peptide complexes does not reflect a failure to interact productively with DM

J Immunol

Biochemical characterization of the human diabetes-associated HLA-DQ8 allelic product: similarity to the major histocompatibility complex class II I-A(g)7 protein of non-obese diabetic mice

Eur J Immunol

Molecular characterization of the diabetes-associated mouse MHC class II protein, I-Ag7

Int Immunol

Beta 57-Asp plays an essential role in the unique SDS stability of HLA- DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC allele associated with protection from insulin-dependent diabetes mellitus

J Immunol

Identification of two distinct properties of class II major histocompatibility complex-associated peptides

Proc Natl Acad Sci U S A

Beta 57-Asp plays an essential role in the unique SDS stability of HLA- DQA10102/DQB10602 alpha beta protein dimer, the class II MHC allele associated with protection from insulin-dependent diabetes mellitus