Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?

Diabetologia. 2021 Jan;64(1):15-25. doi: 10.1007/s00125-020-05298-y. Epub 2020 Oct 21.

Abstract

Available evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes. Genetic susceptibility linked to HLA Class II lends strong support. Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8+ T cells. While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Functional arguments from ex vivo and in vitro human studies and in vivo 'humanised' mouse models are instead neutral or against a T cell role. Clinical support is provided by the appearance of islet autoantibodies before disease onset. The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes. Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk. Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the 'benign' islet autoimmunity of healthy individuals. Graphical abstract.

Keywords: Autoantibodies; Autoimmunity; Beta cells; Endotypes; HLA; Immunotherapy; Insulitis; Islets; Pancreas; Review; T cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset*
  • Animals
  • Autoimmunity
  • CD8-Positive T-Lymphocytes / immunology
  • Diabetes Mellitus, Type 1 / immunology*
  • Genetic Predisposition to Disease
  • Histocompatibility Antigens Class I / analysis
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Humans
  • Islets of Langerhans / immunology
  • Mice
  • T-Lymphocytes / immunology*
  • Young Adult

Substances

  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II