Major Histocompatibility Complex Class II Molecules Function as a Template for the Processing of a Partially Processed Insulin Peptide into a T-cell Epitope

Lang, Ying; Forquet, Frédérique; Speck, Edwin R.; Blum, Janice S.; Delovitch, Terry L.

doi:10.2337/diab.45.12.1711

Cited by 4 publications

(4 citation statements)

References 35 publications

(57 reference statements)

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“…In contrast, a non-fixed B cell line was able to activate T cells, demonstrating that intermediates required further processing within the endocytic compartments in order to become functionally active [19]. Therefore, we mimicked the destination of non-reduced proinsulin within the antigen-processing compartment in an in vitro digestion experiment and incubated proinsulin with purified cathepsins, CatD, G, S, and V, which have endoprotease activity.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients

et al. 2011

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Autoantigenic peptides resulting from self-proteins such as proinsulin are important players in the development of type 1 diabetes mellitus (T1D). Self-proteins can be processed by cathepsins (Cats) within endocytic compartments and loaded to major histocompatibility complex (MHC) class II molecules for CD4+ T cell inspection. However, the processing and presentation of proinsulin by antigen-presenting cells (APC) in humans is only partially understood. Here we demonstrate that the processing of proinsulin by B cell or myeloid dendritic cell (mDC1)-derived lysosomal cathepsins resulted in several proinsulin-derived intermediates. These intermediates were similar to those obtained using purified CatG and, to a lesser extent, CatD, S, and V in vitro. Some of these intermediates polarized T cell activation in peripheral blood mononuclear cells (PBMC) from T1D patients indicative for naturally processed T cell epitopes. Furthermore, CatG activity was found to be elevated in PBMC from T1D patients and abrogation of CatG activity resulted in functional inhibition of proinsulin-reactive T cells. Our data suggested the notion that CatG plays a critical role in proinsulin processing and is important in the activation process of diabetogenic T cells.

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Section: Resultsmentioning

confidence: 99%

Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients

et al. 2011

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“…Furthermore, when performing experiments with inhibitors, only aspartyl proteases under acidic conditions were involved in PI processing, not cysteine or serine proteases. In additional studies from the same group, processing of A1-A14/B1-B16 by CatD, but not of the whole PI protein, increased T cell activation [84]. The aspartyl protease CatE is speculated to unlock cleavage within the PI protein and CatD further digests these fragments into suitable MHC class II-bound T cell epitopes.…”

Section: Processing Of (Pro)-insulin By Cathepsinsmentioning

confidence: 94%

“…This peptide (A1-A14/B7-B15) is referred to as the minimal T cell epitope necessary to stimulate an insulin-reactive human T cell clone with an important recognition site containing glutamic acid (E) at position A4 [82,83]. Lang et al demonstrated using fixed BLC that porcine insulin (PI)-derived intermediates do not activate T cells, demonstrating that intermediates have to be further digested to result in a T cell epitope [84]. Similar results were found using A1-A14/B1-B16; when this peptide bound to MHC class II and was processed intracellularly, T cell activation occurred, but not when the peptide was degraded extracellularly and added to fixed APC.…”

Section: Processing Of (Pro)-insulin By Cathepsinsmentioning

confidence: 99%

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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SummaryBoth CD4 + and CD8 + T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4 + T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells.

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“…Ii serves a dual purpose in protecting the ligand-binding groove of class II complexes, as well as guiding class II molecules to endocytic compartments rich in antigenic peptides. Studies of Ii processing may provide some insights into the processing environment encountered by endogenous antigens within endosomes and lysosomes, as both cysteine and aspartic cathepsins have been implicated in Ii degradation (14)(15)(16). Studies using mice genetically targeted to inactivate cathepsin S suggest this protease functions at a late stage of Ii processing within professional APCs, whereas cathepsin L appears important in catalyzing this terminal reaction within thymic cells (17).…”

Section: Introductionmentioning

confidence: 99%

Cytoplasmic Processing Is a Prerequisite for Presentation of an Endogenous Antigen by Major Histocompatibility Complex Class II Proteins

Lich

Elliott

Blum

2000

The Journal of Experimental Medicine

130

115

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Biochemical and functional studies have demonstrated major histocompatibility complex (MHC) class II–restricted presentation of select epitopes derived from cytoplasmic antigens, with few insights into the processing reactions necessary for this alternate pathway. Efficient presentation of an immunodominant epitope derived from glutamate decarboxylase (GAD) was observed regardless of whether this antigen was delivered exogenously or via a cytoplasmic route into human histocompatibility leukocyte antigen class II–DR4+ antigen-presenting cells. Presentation of exogenous as well as cytoplasmic GAD required the intersection of GAD peptides and newly synthesized class II proteins. By contrast, proteolytic processing of this antigen was highly dependent upon the route of antigen delivery. Exogenous GAD followed the classical pathway for antigen processing, with an absolute requirement for endosomal/lysosomal acidification as well as cysteine and aspartyl proteases resident within these organelles. Presentation of endogenous GAD was dependent upon the action of cytoplasmic proteases, including the proteasome and calpain. Thus, translocation of processed antigen from the cytoplasm into membrane organelles is necessary for class II–restricted presentation via this alternate pathway. Further trimming of these peptides after translocation was mediated by acidic proteases within endosomes/lysosomes, possibly after or before class II antigen binding. These studies suggest that processing of exogenous and cytoplasmic proteins occurs through divergent but overlapping pathways. Furthermore, two cytoplasmic proteases, the proteasome and calpain, appear to play important roles in MHC class II–restricted antigen presentation.

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Major Histocompatibility Complex Class II Molecules Function as a Template for the Processing of a Partially Processed Insulin Peptide into a T-cell Epitope

Cited by 4 publications

References 35 publications

Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients

Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Cytoplasmic Processing Is a Prerequisite for Presentation of an Endogenous Antigen by Major Histocompatibility Complex Class II Proteins

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