Dendritic Cells Guide Islet Autoimmunity through a Restricted and Uniquely Processed Peptidome Presented by High-Risk HLA-DR

Abstract

Identifying T cell epitopes of islet autoantigens is important for understanding type 1 diabetes (T1D) immunopathogenesis and to design immune monitoring and intervention strategies in relationship to disease progression. Naturally processed T cell epitopes have been discovered by elution from HLA-DR4 of pulsed B lymphocytes. The designated professional APC directing immune responses is the dendritic cell (DC). To identify naturally processed epitopes, monocyte-derived DC were pulsed with preproinsulin (PPI), glutamic acid decarboxylase (65-kDa isoform; GAD65), and insulinoma-associated Ag-2 (IA-2), and peptides were eluted of HLA-DR3 and -DR4, which are associated with highest risk for T1D development. Proteome analysis confirmed uptake and processing of islet Ags by DC. PPI peptides generated by DC differed from those processed by B lymphocytes; PPI signal-sequence peptides were eluted from HLA-DR4 and -DR3/4 that proved completely identical to a primary target epitope of diabetogenic HLA-A2–restricted CD8 T cells. HLA-DR4 binding was confirmed. GAD65 peptides, eluted from HLA-DR3 and -DR4, encompassed two core regions overlapping the two most immunodominant and frequently studied CD4 T cell targets. GAD65 peptides bound to HLA-DR3. Strikingly, the IA-2 ligandome of HLA-DR was exclusively generated from the extracellular part of IA-2, whereas most previous immune studies have focused on intracellular IA-2 epitopes. The newly identified IA-2 peptides bound to HLA-DR3 and -DR4. Differential T cell responses were detected against the newly identified IA-2 epitopes in blood from T1D patients. The core regions to which DC may draw attention from autoreactive T cells are largely distinct and more restricted than are those of B cells. GAD65 peptides presented by DC focus on highly immunogenic T cell targets, whereas HLA-DR–binding peptides derived from IA-2 are distinct from the target regions of IA-2 autoantibodies.

Transcriptomic Segregation of Human Autoantigens Useful for the Diagnosis of Autoimmune Diseases

“…Although T1D is classified as a Group I disease, until recently it was not recognized to have pathogenic autoantibodies. However, newer information suggests that IA2, a cell surface molecule, is a target of B- and T-cell responses [52, 53] and may be involved in pathogenesis. It is also possible that transcriptomic analysis could be used to identify novel candidate autoantigens in Group I disorders.…”

“…Two other targets, IA2 and IA2β are cell surface proteins containing both extracellular and intracellular regions, which are encoded by 950 and 977 amino acids, respectively. Interestingly, recent evidence suggests that IA2 is a target of B- and T-cell responses [52, 53] and may be involved in T1D pathogenesis. ZnT8 is a transmembrane protein of 369 amino acids found on intracellular vesicles.…”

Fulminant type 1 diabetes: A comprehensive review of an autoimmune condition

“…These dendritic cells are able to present MHC class I and II molecules and prompt effector leukocytes infiltration through a Batf3 depending pathway, which conduce to the autoimmunity progress against mice islet cells 68 . In addition, an investigation on human high risk HLA‐DR molecules indicated dendritic cells are capable of presenting islet epitopes bound with susceptible HLA‐DR molecules, which manifest the crucial initiator role of dendritic cells in islet autoimmunity 70 . However, no investigation on dendritic cells functioning in FT1D patients was reported up to now.…”

The elusive role of B lymphocytes and islet autoantibodies in (human) type 1 diabetes

“…B lymphocytes are reported to be present in small numbers in early insulitis but are recruited to islets as beta cell death progresses, suggesting that they are a consequence, rather than cause, of insulitis [13]. B lymphocytes take up and process antigens in a concentration-dependent manner and are more than a thousand times less efficient than dendritic cells at presenting antigens if they do not happen to express the B cell receptor for a particular islet autoantigen [14]. For B lymphocytes to get involved, they must first be activated by T cells that are primed prior to seroconversion.…”