Peptidomic analysis of type 1 diabetes associated HLA‐DQ molecules and the impact of HLA‐DM on peptide repertoire editing

Zhou, Zemin; Reyes-Vargas, Eduardo; Escobar, Hernando Criollo; Chang, Kuan Y.; Barker, Adam P.; Rockwood, Alan L.; Delgado, Julio; Xiao, He; Jensen, Peter E.

doi:10.1002/eji.201646656

Cited by 15 publications

(26 citation statements)

References 58 publications

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“…In a study of DR3-expressing T2 cells transfected with different levels of DM, Alvaro-Benito et al found that higher DM expression was associated with presentation of MHC-II-bound peptides with lower predicted MHC-II binding affinity (51). In a study comparing the peptide repertoires of 293T cells transfected with HLA-DQ molecules differentially associated with type 1 diabetes, Zhou et al found that in the absence of DM, peptides with lower binding affinity and faster dissociation were presented (76). These studies agree with our data with respect to DM-sensitive epitopes, in which peptides eluted only in the presence of DO were determined to be more sensitive to DM-mediated exchange.…”

Section: Discussionmentioning

confidence: 99%

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

Nanaware

Jurewicz

Leszyk

et al. 2019

Molecular & Cellular Proteomics

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In BriefComprehensive analysis of MHC-II immunopeptidomes from cells lacking DO (human HLA-DO or murine H2-O) shows that DO controls the diversity of the MHC-II peptide repertoire. DO expression leads to presentation of a broader distribution of peptides, with many low-abundance epitopes presented only in the presence of DO. We suggest that regulated expression of DO allows the immune system to maintain tolerance to a wide variety of self-antigens and allows for an immune response focused on immunodominant antigens for pathogen recognition. Highlights• MHC-II-bound peptide repertoires from DO-sufficient and DO-deficient cells.• Fewer unique peptides and core epitopes were presented in the absence of DO.• Immunopeptidome differences appeared to result from reduced DM editing.• DO-dependent self-epitopes elicited CD4 T cell responses in mice.

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Section: Discussionmentioning

confidence: 99%

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

Nanaware

Jurewicz

Leszyk

et al. 2019

Molecular & Cellular Proteomics

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“…HLA/peptide complex and TCR binding determines the specificity of immune response [44], [45], [46]. HLA genotyping in 6 T1D patients (Table S1) indicated that alleles such as A*24:02 , B*58:01:01 , C*03:02 , DRB1*03:01 , DRB1*09:01:02 , DQB1*03:02:01 , and DQB1*02:01:01 are frequently expressed in these patients, suggesting that these types of HLAs may play roles in T1D biogenesis.…”

Section: Discussionmentioning

confidence: 99%

T Cell Repertoire Diversity is Decreased in Type 1 Diabetes Patients

Tong¹,

Li²,

Zhang³

et al. 2016

Genomics, Proteomics &Amp; Bioinformatics

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Type 1 diabetes mellitus (T1D) is an immune-mediated disease. The autoreactive T cells in T1D patients attack and destroy their own pancreatic cells. In order to systematically investigate the potential autoreactive T cell receptors (TCRs), we used a high-throughput immune repertoire sequencing technique to profile the spectrum of TCRs in individual T1D patients and controls. We sequenced the T cell repertoire of nine T1D patients, four type 2 diabetes (T2D) patients, and six nondiabetic controls. The diversity of the T cell repertoire in T1D patients was significantly decreased in comparison with T2D patients (P = 7.0E−08 for CD4+ T cells, P = 1.4E−04 for CD8+ T cells) and nondiabetic controls (P = 2.7E−09 for CD4+ T cells, P = 7.6E−06 for CD8+ T cells). Moreover, T1D patients had significantly more highly-expanded T cell clones than T2D patients (P = 5.2E−06 for CD4+ T cells, P = 1.9E−07 for CD8+ T cells) and nondiabetic controls (P = 1.7E−07 for CD4+ T cells, P = 3.3E−03 for CD8+ T cells). Furthermore, we identified a group of highly-expanded T cell receptor clones that are shared by more than two T1D patients. Although further validation in larger cohorts is needed, our data suggest that T cell receptor diversity measurements may become a valuable tool in investigating diabetes, such as using the diversity as an index to distinguish different types of diabetes.

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“…Within the pathway, the human leukocyte antigen-DM (HLA-DM) protein enhances peptide loading of MHCII complexes by differentially catalyzing peptide exchange reactions on classical MHCII molecules (3)(4)(5)(6)(7)(8)(9)(10). Through this action, HLA-DM markedly impacts the specificity of antigen presentation by continuously proofreading the peptide-MHCII complexes that are en route for presentation to CD4 ϩ T cells (8,9,(11)(12)(13).…”

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confidence: 99%

HLA-DM catalytically enhances peptide dissociation by sensing peptide–MHC class II interactions throughout the peptide-binding cleft

Reyes-Vargas

Barker

Zhou

et al. 2020

Journal of Biological Chemistry

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Human leukocyte antigen-DM (HLA-DM) is an integral component of the major histocompatibility complex class II (MHCII) antigen-processing and -presentation pathway. HLA-DM shapes the immune system by differentially catalyzing peptide exchange on MHCII molecules, thereby editing the peptide-MHCII (pMHCII) repertoire by imposing a bias on the foreign and self-derived peptide cargos that are presented on the cell surface for immune surveillance and tolerance induction by CD4+ T cells. To better understand DM selectivity, here we developed a real-time fluorescence anisotropy assay to delineate the pMHCII intrinsic stability, DM-binding affinity, and catalytic turnover, independent kinetic parameters of HLA-DM enzymatic activity. We analyzed prominent pMHCII contacts by differentiating the kinetic parameters in pMHCII homologs, observing that peptide interactions throughout the MHCII-binding cleft influence both the rate of peptide dissociation from the DM-pMHCII catalytic complex and the binding affinity of HLA-DM for a pMHCII. We show that the intrinsic stability of a pMHCII linearly correlates with DM catalytic turnover, but is nonlinearly correlated with its binding affinity. Surprisingly, interactions at the peptides N terminus up to and including MHCII position one (P1) anchor affected the catalytic turnover, suggesting that the active DM-pMHCII catalytic complex operates on pMHCII complexes with full peptide occupancy. Furthermore, interactions at the peptide C terminus modulated DM-binding affinity, suggesting distal communication between peptide interactions with the MHCII and the DM-pMHCII binding interface. Our results imply an intimate linkage between the DM-pMHCII interface and peptide-MHCII interactions throughout the peptide-binding cleft.

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Peptidomic analysis of type 1 diabetes associated HLA‐DQ molecules and the impact of HLA‐DM on peptide repertoire editing

Cited by 15 publications

References 58 publications

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

T Cell Repertoire Diversity is Decreased in Type 1 Diabetes Patients

HLA-DM catalytically enhances peptide dissociation by sensing peptide–MHC class II interactions throughout the peptide-binding cleft

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