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"DeLong, Thomas"
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Recognition of Multiple Hybrid Insulin Peptides by a Single Highly Diabetogenic T-Cell Receptor
The mechanisms underlying the major histocompatibility complex class II (MHCII) type 1 diabetes (T1D) association remain incompletely understood. We have previously shown that thymocytes expressing the highly diabetogenic, I-A g7 -restricted 4.1-T-cell receptor (TCR) are MHCII-promiscuous, and that, in MHCII-heterozygous mice, they sequentially undergo positive and negative selection/Treg deviation by recognizing pro- and anti-diabetogenic MHCII molecules on cortical thymic epithelial cells and medullary hematopoietic antigen-presenting cells (APCs), respectively. Here, we use a novel autoantigen discovery approach to define the antigenic specificity of this TCR in the context of I-A g7 . This was done by screening the ability of random epitope–GS linker–I- A β g 7 chain fusion pools to form agonistic peptide–MHCII complexes on the surface of I- A α d chain-transgenic artificial APCs. Pool deconvolution, I-A g7 -binding register-fixing, TCR contact residue mapping, and alanine scanning mutagenesis resulted in the identification of a 4.1-TCR recognition motif XL(G/A)XEXE(D/E)X that was shared by seven agonistic hybrid insulin peptides (HIPs) resulting from the fusion of several different chromogranin A and/or insulin C fragments, including post-translationally modified variants. These data validate a novel, highly sensitive MHCII-restricted epitope discovery approach for orphan TCRs and suggest thymic selection of autoantigen-promiscuous TCRs as a mechanism for the murine T1D–I-A g7 -association.
Journal Article
الطيران بلا شبكة أمان : حول الخوف من التغيير إلى وقود للنجاح
في جميع أجزاء هذا الكتاب، يستخدم المؤلف هذا المصطلح الإ وو الانجاز ومصطلحات أخرى بشكل متبادل للإشارة إلى النوع الذي بحاجة شديدة إلى تحقيق إنجازات. توافق اهتمام المؤلف بهؤلاء المهنيين مع ما للمؤلف من استشارات وكتابات متعلقة بعملية التغير. بينما استمع المؤلف وتعلم وجرب تطبيق مبادئ نظرية التغيير لمواقف تشتمل على مهنيين متعطشين للإنجازات، وبدأ يطور عملية تغيير لهذه المجموعة، عملية تساعدهم على التعلم والنمو بدلا من الركود.
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Chromogranin A is an autoantigen in type 1 diabetes
The identity of self antigens targeted in various autoimmune diseases is often unknown. Haskins and colleagues identify a chromagranin A epitope whose presentation by I-A
g7
involves an unusual peptide-binding mode.
Autoreactive CD4
+
T cells are involved in the pathogenesis of many autoimmune diseases, but the antigens that stimulate their responses have been difficult to identify and in most cases are not well defined. In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have identified the peptide WE14 from chromogranin A (ChgA) as the antigen for highly diabetogenic CD4
+
T cell clones. Peptide truncation and extension analysis shows that WE14 bound to the NOD mouse major histocompatibility complex class II molecule I-A
g7
in an atypical manner, occupying only the carboxy-terminal half of the I-A
g7
peptide-binding groove. This finding extends the list of T cell antigens in type 1 diabetes and supports the idea that autoreactive T cells respond to unusually presented self peptides.
Journal Article
Characterization of Human CD4 T Cells Specific for a C-Peptide/C-Peptide Hybrid Insulin Peptide
Hybrid Insulin Peptides (HIPs), which consist of insulin fragments fused to other peptides from β-cell secretory granule proteins, are CD4 T cell autoantigens in type 1 diabetes (T1D). We have studied HIPs and HIP-reactive CD4 T cells extensively in the context of the non-obese diabetic (NOD) mouse model of autoimmune diabetes and have shown that CD4 T cells specific for HIPs are major contributors to disease pathogenesis. Additionally, in the human context, HIP-reactive CD4 T cells can be found in the islets and peripheral blood of T1D patients. Here, we performed an in-depth characterization of the CD4 T cell response to a C-peptide/C-peptide HIP (HIP11) in human T1D. We identified the TCR expressed by the previously-reported HIP11-reactive CD4 T cell clone E2, which was isolated from the peripheral blood of a T1D patient, and determined that it recognizes HIP11 in the context of HLA-DQ2. We also identified a HIP11-specific TCR directly in the islets of a T1D donor and demonstrated that this TCR recognizes a different minimal epitope of HIP11 presented by HLA-DQ8. We generated and tested an HLA-DQ2 tetramer loaded with HIP11 that will enable direct ex vivo interrogation of CD4 T cell responses to HIP11 in human patients and control subjects. Using mass spectrometric analysis, we confirmed that HIP11 is present in human islets. This work represents an important step in characterizing the role of CD4 T cell responses to HIPs in human T1D.
Journal Article
Insulin B-chain hybrid peptides are agonists for T cells reactive to insulin B:9-23 in autoimmune diabetes
Insulin is considered to be a key antigenic target of T cells in Type 1 Diabetes (T1D) and autoimmune diabetes in the NOD mouse with particular focus on the B-chain amino acid sequence B:9-23 as the primary epitope. Our lab previously discovered that hybrid insulin peptides (HIPs), comprised of insulin C-peptide fragments fused to other β-cell granule peptides, are ligands for several pathogenic CD4 T cell clones derived from NOD mice and for autoreactive CD4 T cells from T1D patients. A subset of CD4 T cell clones from our panel react to insulin and B:9-23 but only at high concentrations of antigen. We hypothesized that HIPs might also be formed from insulin B-chain sequences covalently bound to other endogenously cleaved ß-cell proteins. We report here on the identification of a B-chain HIP, termed the 6.3HIP, containing a fragment of B:9-23 joined to an endogenously processed peptide of ProSAAS, as a strong neo-epitope for the insulin-reactive CD4 T cell clone BDC-6.3. Using an I-A g7 tetramer loaded with the 6.3HIP, we demonstrate that T cells reactive to this B-chain HIP can be readily detected in NOD mouse islet infiltrates. This work suggests that some portion of autoreactive T cells stimulated by insulin B:9-23 may be responding to B-chain HIPs as peptide ligands.
Journal Article
The immunology of type 1 diabetes
Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.The first immune-targeted drug for type 1 diabetes (T1D), teplizumab, received regulatory approval by the US FDA in 2022. In this Review, Herold, Walker and colleagues examine the immune mechanisms that underpin T1D and provide an overview of immune-targeted strategies for T1D that are currently in development.
Journal Article
The insulin secretory granule is a hotspot for autoantigen formation in type 1 diabetes
In type 1 diabetes, the insulin-producing beta cells of the pancreas are destroyed through the activity of autoreactive T cells. In addition to strong and well-documented HLA class II risk haplotypes, type 1 diabetes is associated with noncoding polymorphisms within the insulin gene locus. Furthermore, autoantibody prevalence data and murine studies implicate insulin as a crucial autoantigen for the disease. Studies identify secretory granules, where proinsulin is processed into mature insulin, stored and released in response to glucose stimulation, as a source of antigenic epitopes and neoepitopes. In this review, we integrate established concepts, including the role that susceptible HLA and thymic selection of the T cell repertoire play in setting the stage for autoimmunity, with emerging insights about beta cell and insulin secretory granule biology. In particular, the acidic, peptide-rich environment of secretory granules combined with its array of enzymes generates a distinct proteome that is unique to functional beta cells. These factors converge to generate non-templated peptide sequences that are recognised by autoreactive T cells. Although unanswered questions remain, formation and presentation of these epitopes and the resulting immune responses appear to be key aspects of disease initiation. In addition, these pathways may represent important opportunities for therapeutic intervention.
Graphical Abstract
Journal Article
Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes
Analysis of T cells isolated from patients with and without type 1 diabetes reveals reactivity to a range of native as well as post-translationally modified self-antigens only in individuals with T1D.
A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood–derived T cells
1
,
2
,
3
, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis
4
,
5
,
6
,
7
,
8
, the identification of autoreactive CD8
+
T cells
in situ,
in islets of human leukocyte antigen (HLA)-A2
+
donors
9
and isolation and identification of DQ8 and DQ2–DQ8 heterodimer–restricted, proinsulin-reactive CD4
+
T cells grown from islets of a single donor with T1D
10
. Here we present an analysis of 50 of a total of 236 CD4
+
and CD8
+
T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.
Journal Article
Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion
T cell–mediated destruction of insulin-producing β cells in the pancreas causes type 1 diabetes (T1D). CD4 T cell responses play a central role in β cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in β cell secretory granules. These hybrid insulin peptides (HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in β cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.
Journal Article