Central Role of Defective Interleukin-2 Production in the Triggering of Islet Autoimmune Destruction

• Published in: Immunity (Cambridge, Mass.) Vol. 28; no. 5; pp. 687 - 697
• Main Authors: Tang, Qizhi, Adams, Jason Y., Penaranda, Cristina, Melli, Kristin, Piaggio, Eliane, Sgouroudis, Evridiki, Piccirillo, Ciriaco A., Salomon, Benoit L., Bluestone, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2008; Elsevier Limited
• Subjects: Animals; Autoimmunity; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell Survival; CELLIMMUNO; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Insulin; Interleukin-2 - immunology; Interleukin-2 - metabolism; Interleukin-2 Receptor alpha Subunit - immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Islets of Langerhans - immunology; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphocyte Activation; Medical research; Mice; Mice, Inbred NOD; MOLIMMUNO; Pancreas; Proto-Oncogene Proteins c-bcl-2 - immunology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rodents; T cell receptors; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; MOLIMMUNO; CELLIMMUNO
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2008.03.016

The dynamics of CD4 + effector T cells (Teff cells) and CD4 +Foxp3 + regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.