Shuffling peptides to create T‐cell epitopes: does the immune system play cards?

Mannering, Stuart I.; So, Michelle; Elso, Colleen M.; Kay, Thomas

doi:10.1111/imcb.1015

Cited by 6 publications

(11 citation statements)

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“…More than a decade ago, it was shown that the proteasome generates spliced peptides by joining non‐contiguous peptide fragments via reverse proteolysis, generating neoantigens that are presented by MHC class I and recognized by tumour‐infiltrating CD8 T cells . The discovery of spliced peptides and HIPs illustrates the previously unrecognized complexity of the proteome and the ever‐expanding boundaries of antigen diversity . In this article, we will review the growing number of manuscripts currently available that describe HIPs and their role as autoantigens and discuss the possible mechanisms that may lead to the formation of hybrid peptides in vivo .…”

Section: Introductionmentioning

confidence: 99%

HIPs and HIP-reactive T cells

Wiles

Delong

2019

Clinical and Experimental Immunology

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Mounting evidence implicates hybrid insulin peptides (HIPs) as important autoantigens in the development of type 1 diabetes (T1D). These fusion peptides formed between insulin and other pancreatic beta cell-derived peptides contain non-genomically encoded amino acid sequences, making them plausible targets for autoreactive T cells in T1D. HIPs are detectable by mass spectrometry in human and murine islets and are targeted by diabetes-inducing T cells in non-obese diabetic mice as well as by T cells isolated from the residual pancreatic islets of human organ donors with T1D. The discovery of HIPs comes with numerous new challenges, as well as opportunities to study the pathogenesis of T1D. Here we review the original discovery of HIPs and describe recent studies investigating the role of HIP-reactive T cells in the development of diabetes.We also discuss potential mechanisms that may be responsible for the generation of HIPs in beta cells and describe challenges that need to be addressed in the field of mass spectrometry to enable the discovery of new HIPs. The identification of these potentially disease-driving antigens in T1D is of key interest to the field as it may provide new tools to predict, prevent and potentially reverse the disease.

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Section: Introductionmentioning

confidence: 99%

HIPs and HIP-reactive T cells

Wiles

Delong

2019

Clinical and Experimental Immunology

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“…Responses to neoepitopes, that form in peripheral tissues, may explain how central, or thymic, tolerance is unable to prevent autoimmunity. The role of neoepitopes in T1D has been the subject of several reviews, including Mannering et al ., 9,94,95 James et al ., 96 Pugliese 97 and van Lummel et al 98…”

Section: T‐cell Responses To Ppi‐derived Neoepitopesmentioning

confidence: 99%

Insulin’s other life: an autoantigen in type 1 diabetes

Mannering

Bhattacharjee

2021

Immunol. Cell Biol.

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One hundred years ago, Frederick Banting, John Macleod, Charles Best and James Collip, and their collaborators, discovered insulin. This discovery paved the way to saving countless lives and ushered in the “Insulin Era.” Since the discovery of insulin, we have made enormous strides in understanding its role in metabolism and diabetes. Insulin has played a dramatic role in the treatment of people with diabetes; particularly type 1 diabetes (T1D). Insulin replacement is a life‐saving therapy for people with T1D and some with type 2 diabetes. T1D is an autoimmune disease caused by the T‐cell‐mediated destruction of the pancreatic insulin‐producing beta cells that leads to a primary insulin deficiency. It has become increasingly clear that insulin, and its precursors preproinsulin (PPI) and proinsulin (PI), can play another role—not as a hormone but as an autoantigen in T1D. Here we review the role played by the products of the INS gene as autoantigens in people with T1D. From many elegant animal studies, it is clear that T‐cell responses to insulin, PPI and PI are essential for T1D to develop. Here we review the evidence that autoimmune responses to insulin and PPI arise in people with T1D and discuss the recently described neoepitopes derived from the products of the insulin gene. Finally, we look forward to new approaches to deliver epitopes derived from PPI, PI and insulin that may allow immune tolerance to pancreatic beta cells to be restored in people with, or at risk of, T1D.

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“…These neoepitopes are formed by the fusion of two peptide fragments in beta cells. The HIPs reported by Delong and colleagues were all fusions of parts of proinsulin C-peptide with other beta cell-granule components, such as islet amyloid polypeptide (IAPP) 2 (reviewed in [10,32]). The mechanism that leads to the formation of HIPs is unclear, but it is believed to result from transpeptidation (in a similar manner to the formation of 'spliced' CD8 + T cell epitopes) (reviewed in [32]).…”

Section: Recent Advances In Type 1 Diabetes-associated T Cell Neoepitmentioning

confidence: 99%

“…The HIPs reported by Delong and colleagues were all fusions of parts of proinsulin C-peptide with other beta cell-granule components, such as islet amyloid polypeptide (IAPP) 2 (reviewed in [10,32]). The mechanism that leads to the formation of HIPs is unclear, but it is believed to result from transpeptidation (in a similar manner to the formation of 'spliced' CD8 + T cell epitopes) (reviewed in [32]). Although CD4 + T cells that responded to HIPs were first discovered in the NOD mouse, two laboratories have isolated human islet-infiltrating CD4 + T cells that respond to HIPs, including HLA-DQ8-restricted CD4 + T cell clones [23].…”

Section: Recent Advances In Type 1 Diabetes-associated T Cell Neoepitmentioning

confidence: 99%

“…Our challenge now is to develop high-throughput systems to identify neoepitopes and determine whether responses against neoepitopes drive autoimmune beta cell destruction in type 1 diabetes. New approaches for the identification of neoepitopes will need to accommodate the inconvenient truth that these molecules can be formed in a variety of ways [23,29,32], making neoepitope prediction almost impossible.…”

Section: Future Directions In Identifying and Validating Neoepitopesmentioning

confidence: 99%

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Neoepitopes: a new take on beta cell autoimmunity in type 1 diabetes

2018

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Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of pancreatic insulin-producing beta cells. The epitopes recognised by pathogenic T cells in human type 1 diabetes are poorly defined; however, a growing body of evidence suggests that T cell responses against neoepitopes contribute to beta cell destruction in type 1 diabetes. Neoepitopes are formed when self-proteins undergo post-translational modification to create a new epitope that is recognised by T-or B cells. Here we review the role of human T cell responses against neoepitopes in the immune pathogenesis of type 1 diabetes. Specifically, we review the different approaches to identifying neoepitopes relevant to human type 1 diabetes and outline several advances in this field that have occurred over the past few years. We also discuss the application of neoepitopes to the development of antigenspecific therapies for type 1 diabetes and the unresolved challenges that need to be overcome before the full repertoire of neoepitopes recognised by pathogenic human T cells in type 1 diabetes can be determined. This information may then be used to develop antigen-specific therapies for type 1 diabetes and assays to monitor changes in pathogenic, beta cell-specific T cell responses.

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Shuffling peptides to create T‐cell epitopes: does the immune system play cards?

Cited by 6 publications

References 50 publications

HIPs and HIP-reactive T cells

HIPs and HIP-reactive T cells

Insulin’s other life: an autoantigen in type 1 diabetes

Neoepitopes: a new take on beta cell autoimmunity in type 1 diabetes

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