2019
DOI: 10.1126/sciimmunol.aav7517
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How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes

Abstract: In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9–23 peptide contains epitopes for CD4 T cells in both mice and humans. This peptide requires C-terminal mutations for uniform binding in the proper position within the mouse IAg7 or human DQ8 MHCII peptide grooves and for strong CD4 T cell stimulation. Here we present structures showing how these mutations control CD4 T cell receptor (TCR) binding to these MHCII-peptide complexes. Our data reveal striking similarities between mouse … Show more

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Cited by 43 publications
(68 citation statements)
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“…Likely, these differences were mostly due to the added p1 amino acid, whose side chain has often been shown to interact with the T cell receptor in crystal structures of TCR–MHCII–peptide complexes. (e.g., Wang et al, 2019 ).…”
Section: Resultsmentioning
confidence: 99%
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“…Likely, these differences were mostly due to the added p1 amino acid, whose side chain has often been shown to interact with the T cell receptor in crystal structures of TCR–MHCII–peptide complexes. (e.g., Wang et al, 2019 ).…”
Section: Resultsmentioning
confidence: 99%
“…Over several decades, numerous CD4 T cell clones in mice and humans have been identified whose MHCII-presented pancreatic epitopes map to several pancreatic β cell granule proteins; however, as with other autoimmune diseases, natural peptides derived from these proteins were often either inactive or only weakly active in stimulating the clones ( Dallas-Pedretti et al, 1995 ; Stadinski et al, 2010a , b ; Wang et al, 2018 ). Recently, we and others have reported highly stimulatory versions of these peptides in which certain amino acids in the natural peptide have been replaced with other amino acids sometimes derived from the same or different pancreatic proteins ( Babon et al, 2016 ; Crawford et al, 2011 ; Delong et al, 2016 ; Jin et al, 2015 ; Stadinski et al, 2010a , b ; Wang et al, 2018 , 2019 ; Wiles et al, 2017 ; Yang et al, 2014 ). In a few cases, these chimeric peptides have been shown to be present in the pancreas itself ( Wiles et al, 2017 , 2019 ).…”
Section: Introductionmentioning
confidence: 99%
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“…Indeed, much of the evidence for germline-encoded TCR-MHC contacts comes from analyses of Vβ8containing TCRs and structurally related Vβs in humans (Vβ13, 6, 7, 8 encoded by TRBV6, 7, 4, and 12 subfamilies respectively) 2, 5, 6 . While Vβ2 containing TCR-pMHC complex structures were reported earlier 26,27,28,29,30 In previous studies, the most prominent germline contacts involve tyrosine residues (e.g.…”
Section: Discussionmentioning
confidence: 86%
“…Many polymorphic loci identified by genome-wide and disease-association studies and which can potentially underlie susceptibility to T1DM have been linked to immune dysfunctions in dendritic cells such as in cytokine signaling, development and activation, all of which disrupt their tolerogenic properties (Hotta-Iwamura & Tarbell 2016). The recent identification of an insulin B peptide as a trigger of T-regulatory cells in the pancreas provides a promising prospect for targeting TLRs and dendritic cells to suppress autoimmunity in T1DM (Wang et al 2019).…”
Section: Commonalities Between T1dm and Endo Inflammatory Statusmentioning
confidence: 99%