ESPE Yearbook of Paediatric Endocrinology

Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2107208118. https://pubmed.ncbi.nlm.nih.gov/34611019/

Brief Summary: This in vitro study explored the reactivity to preproinsulin of CD8 T cells obtained from pancreatic islets of individuals with and without type 1 diabetes (T1D). The main finding was that CD8 T cells from T1D donors were highly reactive to peptides throughout the entire preproinsulin protein.

This study focused on the cytotoxic CD8 T cells, which play a key role in the pathogenesis of T1D, where they are implicated in beta-cells destruction through self-antigen presentation by HLA class I molecules (1). The first key finding was the huge difference in the number of CD8 T cells between T1D donors and controls, and that CD8 T cells highly specific to preproinsulin are enriched within the islets of a subset of T1D organ donors. Of interest, several different HLA class I molecules emerged to have a role in presenting epitopes throughout the preproinsulin protein to the CD8 T cells. The results are in line with a previous study showing that preproinsulin-specific T cells are present in the pancreatic exocrine compartment of organ donors without diabetes, and during the course of T1D development, they accumulate into insulin-containing islets (2).

Of note, there was variability among T1D organ donors in the frequency of preproinsulin reactive CD8 T cells in the islets. This heterogeneity was associated with certain HLA alleles. The study also showed that multiple HLA class I molecules across HLA-A, -B, and -C can present epitopes of preproinsulin to activate islet derived CD8 T cells.

Many clinical trials have tested proinsulin- or insulin-based therapies to prevent T1D onset and induce tolerance (3). These approaches have proved safe but showed heterogeneous efficacy with subsets of responders. The present study provides important information for the design of future immunotherapy interventions that should consider the use of preproinsulin rather than just insulin or proinsulin and consider participants selection based on HLA typing.

References: 1. Bender C, Rajendran S, von Herrath MG. New Insights Into the Role of Autoreactive CD8 T Cells and Cytokines in Human Type 1 Diabetes. Front Endocrinol (Lausanne) 2021;11:606–43. 2. Bender C, Rodriguez-Calvo T, Amirian N, Coppieters KT, von Herrath MG. The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes. Sci Adv 2020;6:eabc5586. 3. Dayan CM, Korah M, Tatovic D, Bundy BN, Herold KC. Changing the landscape for type 1 diabetes: the first step to prevention. Lancet. 2019;394(10205):1286–1296.