Antigen-specific T cell responses in autoimmune diabetes

Abstract

Autoimmune diabetes is a disease characterized by the selective destruction of insulin-secreting β-cells of the endocrine pancreas by islet-reactive T cells. Autoimmune disease requires a complex interplay between host genetic factors and environmental triggers that promote the activation of such antigen-specific T lymphocyte responses. Given the critical involvement of self-reactive T lymphocyte in diabetes pathogenesis, understanding how these T lymphocyte populations contribute to disease is essential to develop targeted therapeutics. To this end, several key antigenic T lymphocyte epitopes have been identified and studied to understand their contributions to disease with the aim of developing effective treatment approaches for translation to the clinical setting. In this review, we discuss the role of pathogenic islet-specific T lymphocyte responses in autoimmune diabetes, the mechanisms and cell types governing autoantigen presentation, and therapeutic strategies targeting such T lymphocyte responses for the amelioration of disease.

Keywords: T cells; antigen specific therapy; autoantigens; autoimmune diabetes; hybrid insulin peptides.

Figure 1

Overview of immunologic processes leading to enhanced antigen-specific T cell responses in autoimmune diabetes. Environmental factors such as genetic predisposition, viral infections, dietary exposures, and microbiome composition are all risk factors for AD development (top). At the organ level, destruction of pancreatic islets releases self-antigen that drains to pancreatic lymph nodes either as free antigen or loaded to antigen presenting cells (APCs) where it is presented to antigen-specific T cells that subsequently traffic to pancreatic islets to propagate further damage (middle). At the islet level, an unknown insult induces βcell necrosis and antigen release, initiating several pathways to T cell antigen presentation. Antigen may be drained to local lymph nodes either as free antigen or loaded to dendritic cells as above. Alternatively, antigen may enter the vasculature as exosomes for antigen presentation peripherally. Finally, T cell antigen presentation can occur within the islet, mediated by macrophages, dendritic cells, or B cells. Ultimately, T cells enter the islet proper from the periphery to promote killing of βcells through apoptotic mechanisms, further increasing the pool of available self-antigen.