Conserved T cell receptor -chain induces insulin autoantibodies

Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2008; 105(29):10090-10094. DOI: 10.1073/pnas.0801648105
Source: PubMed


A fundamental question is what are the molecular determinants that lead to spontaneous preferential targeting of specific autoantigens in autoimmune diseases, such as the insulin B:9-23 peptide sequence in type 1 diabetes. Anti-insulin B:9-23 T cell clones isolated from prediabetic NOD islets have a conserved Valpha-segment/Jalpha-segment, but no conservation of the alpha-chain N region and no conservation of the Vbeta-chain. Here, we show that the conserved T cell receptor alpha-chain generates insulin autoantibodies when transgenically or retrogenically introduced into mice without its corresponding Vbeta. We suggest that a major part of the mystery as to why islet autoimmunity develops relates to recognition of a primary insulin peptide by a conserved alpha chain T cell receptor.

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Available from: Jean M Jasinski, Dec 27, 2013
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    • "Among these TCRs, the N region sequences of the α-chains were highly variable, and no consistent TCR β-chain usage was apparent. Two anti-insulin B:9–23 TCR α-chains (derived from T-cell clones 12–4.1 and 12–4.4) using the same Vα (TRAV5D-4*04) and Jα (TRAJ53) gene segments, but having unique N region sequences, were capable of inducing insulin autoimmunity in Cα knockout NOD mice (21). In this article, we show that the sequences underlying such induction of insulin autoimmunity are relatively simple. "
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    ABSTRACT: There is accumulating evidence that autoimmunity to insulin B chain peptide, amino acids 9-23 (insulin B:9-23), is central to development of autoimmune diabetes of the NOD mouse model. We hypothesized that enhanced susceptibility to autoimmune diabetes is the result of targeting of insulin by a T-cell receptor (TCR) sequence commonly encoded in the germline. In this study, we aimed to demonstrate that a particular Vα gene TRAV5D-4 with multiple junction sequences is sufficient to induce anti-islet autoimmunity by studying retrogenic mouse lines expressing α-chains with different Vα TRAV genes. Retrogenic NOD strains expressing Vα TRAV5D-4 α-chains with many different complementarity determining region (CDR) 3 sequences, even those derived from TCRs recognizing islet-irrelevant molecules, developed anti-insulin autoimmunity. Induction of insulin autoantibodies by TRAV5D-4 α-chains was abrogated by the mutation of insulin peptide B:9-23 or that of two amino acid residues in CDR1 and 2 of the TRAV5D-4. TRAV13-1, the human ortholog of murine TRAV5D-4, was also capable of inducing in vivo anti-insulin autoimmunity when combined with different murine CDR3 sequences. Targeting primary autoantigenic peptides by simple germline-encoded TCR motifs may underlie enhanced susceptibility to the development of autoimmune diabetes.
    Diabetes 03/2012; 61(4):857-65. DOI:10.2337/db11-1113 · 8.10 Impact Factor
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    ABSTRACT: Mounting evidence suggests insulin is an important and potentially initiating antigen in the pathogenesis of Type 1 diabetes. High-affinity insulin antibodies are found early in disease development and appear to predict progression. Insulin is the only Type 1 diabetes auto-antigen with exclusive pancreatic expression and the only one whose gene maps to a major susceptibility locus. Preclinical studies in rodent models of immune-mediated diabetes show great promise for the possibility of preventing disease by peripheral tolerization. Translation of this evidence to clinical trials of oral, intranasal and parenteral insulin to invoke immune tolerance and prevent diabetes has not proven successful to date, but promising results in a small subset of highest-risk individuals have maintained enthusiasm for this promising prevention strategy. Currently, studies of oral and intranasal insulin are ongoing to determine the optimal dose, timing and target population for Type 1 diabetes prevention.
    Expert Review of Clinical Immunology 01/2009; 5(1):55-62. DOI:10.1586/1744666X.5.1.55 · 2.48 Impact Factor
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    ABSTRACT: ObjectiveThe objective of this study was to define the spectrum of TCR beta chains permissive for T cells with alpha chains containing the conserved TRAV5D-4*04 sequence to target the insulin B:9-23 peptide, a major epitope for initiation of diabetes in the NOD mouse.Materials and methodsWe produced T cell hybridomas from mice with single T cell receptors (BDC12-4.1 TCR α+β+ double transgenic mice and BDC12-4.4 TCR α+β+ double retrogenic mice) or from mice with only the corresponding alpha chains transgene or retrogene and multiple endogenous TCR beta chains.ResultsHybridomas with the complete BDC12-4.1 and BDC12-4.4 T cell receptors, despite having markedly different TCR beta chains, responded to similar B:9-23 peptides. Approximately 1% of the hybridomas from mice with the fixed TRAV5D-4*04 alpha chains and multiple endogenous beta chains responded to B:9-23 peptides while the majority of hybridomas with different beta chains did not respond. There was no apparent conservation of TCR beta chain sequences in the responding hybridomas.ConclusionsApproximately 1% of hybridomas utilizing different TCR β chains paired with the conserved TRAV5D-4*04 containing alpha chains respond to insulin peptide B:9-23. Therefore, TCR beta chain sequences make an important contribution to insulin B:9-23 peptide recognition but multiple beta chain sequences are permissive for recognition.
    Journal of Autoimmunity 08/2009; 33(1-33):42-49. DOI:10.1016/j.jaut.2009.02.003 · 8.41 Impact Factor
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