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 and human CD4 TCRs in their interactions with these ligands. We also show how fusions between fragments of B:9–23 and of proinsulin C-peptide create chimeric peptides with activities as strong or stronger than the mutated insulin peptides. We propose transpeptidation in the lysosome as a mechanism that could accomplish these fusions in vivo, similar to the creation fused peptide epitopes for MHCI presentation shown to occur by transpeptidation in the proteasome. Were this mechanism unique to the pancreas and absent in the thymus, it could provide an explanation for how diabetogenic T cells escape negative selection during development but find their modified target antigens in the pancreas to cause T1D.

Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

“…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 ).…”

“…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 ).…”

“…We have argued ( Jin et al, 2015 ; Wang et al, 2018 , 2019 ) that transpeptidation in the lysosome/endosome compartment is a likely mechanism for generating chimeric epitopes for MHCII, since these organelles contain many cysteine/serine proteases capable of mediating the reaction and, moreover, are the location where most peptides destined for presentation by MHCII are produced. Furthermore, in β cells and other neuroendocrine cells, secretory granules that contain high concentrations of the relevant protein precursors of potential autoantigen epitopes continuously turn over by the process of crinophagy, in which the granules fuse with lysosomes and their contents are degraded by these proteases ( Boudier and Picard, 1976 ; Sandberg and Borg, 2006 ).…”

Novel Vβ specific germline contacts shape an elite controller T cell response

“…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.…”

Co-morbidity of type 1 diabetes and endometriosis: bringing a new paradigm into focus

“…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).…”