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

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.

Graphical abstract

Fig. 1

Evidence for or against a primary pathogenic role for T cells in human type 1 diabetes (T1D). APECED, autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (syndrome); IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (syndrome); This figure is available as part of a downloadable slideset

Fig. 2

Key differences in insulitis and residual ICIs in type 1 diabetes endotypes T1DE1 and T1DE2. (a–d) T1DE1 donors (mostly with a disease onset <13 years old) have few residual ICIs (a; green and red circles) compared with non-ICIs (blue and pink circles). The majority of residual ICIs display significant immune infiltration (a; >15 CD45⁺ cells, green circles); a representative image is shown in (b). This infiltrate is enriched in CD20⁺ B cells and CD8⁺ T cells (c, d). (e–h) T1DE2 donors (mostly with a disease onset ≥13 years old) retain significant residual ICIs (e; red and green circles), the majority of which do not meet the criteria for insulitis (e; red circles). Most ICIs have limited infiltration with CD45⁺ cells (f), the majority of which are CD8⁺ T cells with few CD20⁺ B cells (g, h). Specimens from representative donors from the EADB biobank (https://foulis.vub.ac.be) were immunostained with antibodies against insulin/glucagon/CD45 or glucagon/CD20/CD8 using triple chromogen-based immunohistochemistry similar to that described in [78]. Scale bars, 5 mm (a), 100 μm (b–d, f–h) or 10 mm (e). This figure is available as part of a downloadable slideset