Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?
Alexia CarréSarah J RichardsonEtienne LargerRoberto MallonePublished in: Diabetologia (2020)
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.
Keyphrases
- type diabetes
- induced apoptosis
- endothelial cells
- glycemic control
- insulin resistance
- cell cycle arrest
- stem cells
- induced pluripotent stem cells
- gene expression
- risk assessment
- systemic lupus erythematosus
- endoplasmic reticulum stress
- physical activity
- hepatitis c virus
- mesenchymal stem cells
- pluripotent stem cells
- genome wide
- adipose tissue
- dna methylation
- hiv infected
- bone marrow
- oxidative stress
- dendritic cells
- climate change
- human immunodeficiency virus
- antiretroviral therapy
- sensitive detection
- loop mediated isothermal amplification