Self-Antigen Specificity of Islet-Infiltrating T-cells
Autoreactive T cells specific for beta cell antigens have previously been identified from the peripheral blood of type 1 diabetes (T1D) patients, and immune cells within the pancreatic insulitis lesion been immunophenotyped from human organ donor tissues. However, this report by Babon et al. represents one of the first and most extensive studies of T cell lines grown from handpicked islets from nine organ donors with T1D. Autoreactive targets of CD4+ T cells were determined by measuring cytokine secretion in response to stimulation with whole proteins or specific peptides derived from beta cell antigens.
Indeed, autoreactivity was identified against chromogranin A, preproinsulin, glutamic acid decarboxylase 65 (GAD) GAD555–567, proinsulin76–90, GAD274–286, GAD115–127, and islet antigen (IA)-2545–562. CD4+ T cells were also shown to react with post-translationally modified peptides including citrullinated glucose-regulated protein 78 (GRP78)292–305, citrullinated IAPP65–84, and various hybrid insulin peptides (HIPs). CD8+ T cells reactive against insulin B10–18, IA-2797–805 and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)265–273 peptides were identified by multimer staining and flow cytometry, but surprisingly, reactivity was unknown for 99% of expanded CD8+ T cells. Data such as these expand our knowledge of the autoreactive T cell repertoire at the site of autoimmune destruction in T1D and highlight the need to identify additional antigenic targets of intra-islet T cell, both of which are key steps toward developing targeted therapies that specifically disrupt the activation of autoreactive T cells or restore tolerance in subjects with ongoing autoimmunity to prevent or halt the disease.
Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.
Babon JA, DeNicola ME, Blodgett DM, Crèvecoeur I, Buttrick TS, Maehr R, Bottino R, Naji A, Kaddis J, Elyaman W, James EA, Haliyur R, Brissova M, Overbergh L, Mathieu C, Delong T, Haskins K, Pugliese A, Campbell-Thompson M, Matthews C, Atkinson M, Powers AC, Harlan DM, Kent SC (2016).