The wide diversity and complexity of peptides bound to class II MHC molecules

Suri, Anish; Lovitch, Scott B.; Unanue, Emil R.

doi:10.1016/j.coi.2005.11.002

Cited by 64 publications

(57 citation statements)

References 53 publications

(64 reference statements)

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“…A total of 320 peptides representing 120 distinct families were identified. Class II MHC-associated peptides are often selected in "families," wherein all members share a common 9-mer core that spans residues P1-P9 along with varying lengths of flanking residues in the C-and N-termini (17). As expected, most of the peptide families were derived from ubiquitous self-proteins; and many had been found in our previous reports and are not shown here (7)(8)(9).…”

Section: Characterization Of Naturally Processed I-a G7 -Peptides Fromentioning

confidence: 73%

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Suri¹,

Walters

Rohrs

et al. 2008

The Journal of Immunology

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The diversity of Ags targeted by T cells in autoimmune diabetes is unknown. In this study, we identify and characterize a limited number of naturally processed peptides from pancreatic islet β-cells selected by diabetogenic I-Ag7 molecules of NOD mice. We used insulinomas transfected with the CIITA transactivator, which resulted in their expression of class II histocompatibility molecules and activation of diabetogenic CD4 T cells. Peptides bound to I-Ag7 were isolated and examined by mass spectrometry: some peptides derived from proteins present in secretory granules of endocrine cells, and a number were shared with cells of neuronal lineage. All proteins to which peptides were identified were expressed in β cells from normal islets. Peptides bound to I-Ag7 molecules contained the favorable binding motif characterized by acidic amino acids at the P9 position. The draining pancreatic lymph nodes of prediabetic NOD mice contained CD4 T cells that recognized three different natural peptides. Furthermore, four different peptides elicited CD4 T cells, substantiating the presence of such self-reactive T cells. The overall strategy of identifying natural peptides from islet β-cells opens up new avenues to evaluate the repertoire of self-reactive T cells and its role in onset of diabetes.

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Section: Characterization Of Naturally Processed I-a G7 -Peptides Fromentioning

confidence: 73%

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Suri¹,

Walters

Rohrs

et al. 2008

The Journal of Immunology

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“…The peptides associated with MHC molecules are derived from a broad spectrum of nuclear, cytoplasmic, transmembrane, and even cryptic proteins that are encoded by genes located throughout the genome, with representatives from every chromosome. 7,13,14 Disparity between MHC-matched donor/recipient pairs for specific peptides, that is, the presence of a peptide in the immunopeptidome of the recipient and its absence from that of the donor, or the converse, can elicit T-cell responses that, in turn, can contribute to GVHD/ GVL or, alternatively, to graft rejection. Peptides encoded by polymorphic loci outside the MHC and presented by an MHC molecule are functionally defined as minor H antigens.…”

Section: The Mhc: Establishing Immunologic Identitymentioning

confidence: 99%

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT

Warren

Zhang

et al. 2012

Blood

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The outcome of allogeneic hematopoietic cell transplantation is influenced by donor/recipient genetic disparity at loci both inside and outside the MHC on chromosome 6p. Although disparity at loci within the MHC is the most important risk factor for the development of severe GVHD, disparity at loci outside the MHC that encode minor histocompatibility (H) antigens can elicit GVHD and GVL activity in donor/recipient pairs who are otherwise genetically identical across the MHC. Minor H antigens are created by sequence and structural variations within the genome. The enormous variation that characterizes the human genome suggests that the total number of minor H loci is probably large and ensures that all donor/ recipient pairs, despite selection for identity at the MHC, will be mismatched for many minor H antigens. In addition to mismatch at minor H loci, unrelated donor/ recipient pairs exhibit genetic disparity at numerous loci within the MHC, particularly HLA-DP, despite selection for identity at HLA-A, -B, -C, and -DRB1. Disparity at HLA-DP exists in 80% of unrelated pairs and clearly influences the outcome of unrelated hematopoietic cell transplantation; the magnitude of this effect probably exceeds that associated with disparity at any locus outside the MHC. (Blood. 2012;120(14):2796-2806) IntroductionGenetic nonidentity between donor and recipient is the key to the therapeutic efficacy of allogeneic hematopoietic cell transplantation (HCT) for malignant disease, but it is also the root of GVHD, its primary limitation. Pioneering studies in the late 1960s and early 1970s led to the critical discovery that donor/recipient genetic nonidentity at the MHC on chromosome 6p is the single most important risk factor for the development of severe GVHD. 1 The subsequent implementation of donor selection procedures according to donor/recipient MHC matching established with serologic assays and mixed lymphocyte culture revolutionized the nascent field of allogeneic marrow transplantation and enabled rapid growth during the subsequent decade in the annual number of transplantations performed, as well as considerable improvement in the likelihood of a successful transplantation outcome. Nonetheless, clinically significant GVHD still developed in a sizeable fraction of recipients of bone marrow grafts from sibling donors with whom they were genotypically identical throughout the MHC region on both copies of chromosome 6p. This observation suggested that genetic loci outside the MHC, encoding putative histocompatibility determinants that were collectively referred to as minor histocompatibility (H) antigens, could also influence a recipient's likelihood of developing GVHD or benefitting from GVL activity. 1,2 The intervening years have witnessed steady progress in elucidating the nature of minor H antigens and the genes that encode them and have seen the identification and characterization of other complex genetic loci that also influence histocompatibility in the allogeneic HCT setting. Here, we review the manner in which g...

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“…8 Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4 ϩ T cells that can bind to the MHC class II-peptide complex. 8,9 The conditions under which CD4 ϩ T cells interact with this complex determine whether the immune system reacts with nonresponsiveness, is activated to develop specific antibodies, or is tolerized to suppress antibody responses. 9,10 Therefore, it is crucial to understand which FVIII peptides are presented by MHC class II complexes under conditions of FVIII replacement therapy and how CD4 ϩ T cells interact with MHC class II-FVIII peptide complexes expressed by antigenpresenting cells.…”

Section: Introductionmentioning

confidence: 99%

CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice

Steinitz

Helden

Binder

et al. 2012

Blood

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Today it is generally accepted that B cells require cognate interactions with CD4 IntroductionThe most serious complication in replacement therapy with FVIII products is the development of neutralizing antibodies against FVIII (FVIII inhibitors), which is observed in approximately 25% to 30% of patients with severe hemophilia A. 1 Although several genetic 2 and nongenetic 3 factors that contribute to the risk for patients to develop these antibodies have been identified, why some patients develop antibodies while others do not remains largely unknown.Today it is generally accepted that B cells require cognate interactions with CD4 ϩ T cells to develop high-affinity antibodies against protein antigens. 4,5 In line with this perception, several lines of evidence have supported the involvement of CD4 ϩ T cells in the generation of antibody responses against FVIII in patients with hemophilia A and in murine hemophilia models. 6,7 CD4 ϩ T cells express T-cell receptors that recognize antigen-derived peptides (CD4 ϩ T-cell epitopes) presented by MHC class II molecules, which are expressed on specialized antigen-presenting cells. 8 Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4 ϩ T cells that can bind to the MHC class II-peptide complex. 8,9 The conditions under which CD4 ϩ T cells interact with this complex determine whether the immune system reacts with nonresponsiveness, is activated to develop specific antibodies, or is tolerized to suppress antibody responses. 9,10 Therefore, it is crucial to understand which FVIII peptides are presented by MHC class II complexes under conditions of FVIII replacement therapy and how CD4 ϩ T cells interact with MHC class II-FVIII peptide complexes expressed by antigenpresenting cells. The available information on FVIII peptides presented in the context of specific human MHC class II molecules is limited. Several studies used peripheral blood cells of patients and healthy controls 11 to identify CD4 ϩ T-cell epitopes in the A2 domain, 12 A3 domain, 13 and C2 domain of FVIII. 14 However, these studies lack information on the specific MHC class II molecules associated with the FVIII peptides identified. Jacquemin et al identified T-cell epitopes of FVIII using CD4 ϩ T-cell clones isolated from a mild hemophilia A patient carrying an Arg2150His mutation in the C1 domain of FVIII. 15 All clones recognized FVIII peptides encompassing residue Arg2150. Peptides were presented by HLA-DRB1*0401/HLA-DRB4*01 or HLA-DRDRB1*1501/ HLA-DRB5*0101. One of the peptides identified was a promiscuous epitope that bound to several different HLA-DR proteins. James et al used MHC class II tetramers to analyze FVIII-specific CD4 ϩ T cells obtained from a mild hemophilia A patient carrying an Ala2201Pro mutation in the C2 domain of FVIII. 16 Responses of CD4 ϩ T cells to sequences containing Ala2201 (wild-type), Pro2201 (hemophilic), and other predicted T-cell epitopes were evaluated and resulted in the identification of an HLA-DRB1*0101 restricted T-ce...

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The wide diversity and complexity of peptides bound to class II MHC molecules

Cited by 64 publications

References 53 publications

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Effect of MHC and non-MHC donor/recipient genetic disparity on the outcome of allogeneic HCT

CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice

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