Content area
Full text
About the Authors:
Anmar Khadra
* E-mail: [email protected]
Affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Massimo Pietropaolo
Affiliation: Laboratory of Immunogenetics, University of Michigan, Ann Arbor, Michigan, United States of America
Gerald T. Nepom
Affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America
Arthur Sherman
Affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Introduction
Type 1 Diabetes (T1D) is an autoimmune disorder in which the body's own immune cells (cytotoxic T lymphocytes, CTLs) target the insulin-secreting beta cells in the Islets of Langerhans of the pancreas. These CTLs (including CD8 and CD4 T cells) recognize beta cells and kill them. The process of recognition relies on a complex interaction between a self-molecule peptide, the MHC complex, and T-cell receptors (TCRs). Receptor affinity to peptide-MHC complex (p-MHC) (or T-cell avidity as a whole) varies between different subsets of T cells. High-avidity T cells are implicated in beta-cell destruction, leading to the abolishment of insulin secretion, which is crucial for the regulation of glucose.
The role of T cells as effectors of beta-cell death is undisputed, although formal proof is available mainly in animal models of autoimmune diabetes [1]–[6]. Multiple mechanisms have been invoked to elucidate how beta cells are destroyed. T cells can directly kill beta cells via cell-to-cell contact, through a cytotoxic process, but they can also influence their destruction through other factors, including the release of proinflammatory cytokines, granzyme B, or perforin, and possibly signaling through pathways of programmed cell death [7]–[9]. Several observations suggest that proinflammatory cytokines, such as IL-1, IFN and free radicals are mediators of pancreatic beta-cell death. Autoreactive T cells with potential preferential usage of TCRs responsive to diabetes-related autoantigens may serve as both a potential marker for disease progression and a target for immune manipulation in autoimmune diabetes.
There is also evidence suggesting the involvement of autoreactive regulatory T cells in suppressing islet-specific destructive T-cell activity of differential antigenic specificity locally in the pancreatic draining lymph node, probably via cytokine-mediated modulation of antigen-presenting cells [10]–[12]. In the present work we have elected...