New insights into non-conventional epitopes as T cell targets: The missing link for breaking immune tolerance in autoimmune disease?

J Autoimmun. 2017 Nov;84:12-20. doi: 10.1016/j.jaut.2017.08.001. Epub 2017 Aug 10.


The mechanism by which immune tolerance is breached in autoimmune disease is poorly understood. One possibility is that post-translational modification of self-antigens leads to peripheral recognition of neo-epitopes against which central and peripheral tolerance is inadequate. Accumulating evidence points to multiple mechanisms through which non-germline encoded sequences can give rise to these non-conventional epitopes which in turn engage the immune system as T cell targets. In particular, where these modifications alter the rules of epitope engagement with MHC molecules, such non-conventional epitopes offer a persuasive explanation for associations between specific HLA alleles and autoimmune diseases. In this review article, we discuss current understanding of mechanisms through which non-conventional epitopes may be generated, focusing on several recently described pathways that can transpose germline-encoded sequences. We contextualise these discoveries around type 1 diabetes, the prototypic organ-specific autoimmune disease in which specific HLA-DQ molecules confer high risk. Non-conventional epitopes have the potential to act as tolerance breakers or disease drivers in type 1 diabetes, prompting a timely re-evaluation of models of a etiopathogenesis. Future studies are required to elucidate the disease-relevance of a range of potential non-germline epitopes and their relationship to the natural peptide repertoire.

Publication types

  • Review

MeSH terms

  • Animals
  • Autoantigens / immunology
  • Autoimmunity
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Epitopes, T-Lymphocyte / metabolism*
  • HLA-DQ Antigens / genetics
  • HLA-DQ Antigens / metabolism
  • Humans
  • Immune Tolerance
  • Risk
  • T-Lymphocytes / immunology*


  • Autoantigens
  • Epitopes, T-Lymphocyte
  • HLA-DQ Antigens