Farhan Mithani

Introduction. Type I Diabetes Mellitus (T1DM) is a T-cell mediated autoimmune disease characterized by the destruction of pancreatic beta cells, hypoinsulinemia, and severely altered glucose homeostasis. ^1,2 The destruction of insulin-secreting pancreatic beta cells prevents insulin secretion and, therefore, prevents insulin from regulating glucose homeostasis. The disease etiology of Type 1 Diabetes Mellitus is not completely understood; however, regulatory T cells have a key role in the pathogenesis of Type 1 Diabetes Mellitus.^3,4 During immune homeostasis, regulatory T cells suppress the actions of autoreactive effector T cells, thereby contributing to peripheral tolerance. An imbalance in the activity of effector T cells and regulatory T cells may be crucial in the breakdown of peripheral tolerance, leading to the development of Type 1 Diabetes Mellitus.⁵ Strategies to increase regulatory T cell number and/or function have been viewed as potential therapeutic approaches in treating Type I Diabetes Mellitus. In T1DM, both the number and function of Tregs are reduced. Methods. A focused study of recent research was performed using PubMed for all potentially relevant articles, focusing the study on the number/frequency and/or function of Tregs in patients with T1DM. These studies analyzed the roles of Tregs in the pathogenesis of T1DM. In most studies, the non-obese diabetic mouse model was utilized.⁶ Results. The search identified 12 research articles that investigated the frequency and/or number of Tregs in T1DM animals and patients. These studies illustrated how declining ratios of Tregs/Teffs contributes to the pathogenesis of T1DM by decreasing peripheral tolerance of autoreactive effector T cells.^1,3,7 In addition, several studies pointed to potential therapeutic strategies to increase the Tregs/Teffs ratio, including expanding/activating regulatory T cells with low-dose IL-2, administration of anti-IL-17 antibodies, administration of IL-25, anti-CD3 therapy, and direct infusion of Treg cells. Conclusion. Studies have indicated the deleterious effect that declining regulatory T cells have on the pathogenesis of autoimmune diseases, including T1DM.^1,4,5 Reduced regulatory T cell function and an imbalance in the Treg/Teff response leads to failure to maintain peripheral self-tolerance. The diminished ratio favors the proinflammatory Teff response and the resultant Th1-mediated beta-cell destruction.

1. van Belle TL, Coppieters KT, von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79–118
2. Walker LS (2013) Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun 45:49–57
3. Peterson RA (2012) Regulatory T-cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicol Pathol 40:186–204
4. Battaglia M, Roncarolo MG (2011) Immune intervention with T regulatory cells: past lessons and future perspectives for type 1 diabetes. Semin Immunol 23:182–194
5. Venigalla RK, Guttikonda PJ, Eckstein V, Ho AD, Sertel S, Lorenz HM et al (2012) Identification of a human Th1-like
6. Fontenot JD, GavinMA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336
7. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science (New York, NY) 299:1057–1061