The Role of IL-2 in the pathogenesis and progression of Type I diabetes
Donald Hubbard II
Introduction. Type I diabetes (T1DM) is an autoimmune disease due to destruction of pancreatic beta cells and results in hyperglycemia and hypoinsulinemia.1 It most often develops before the age of 30.2 The major causes of mortality in these patients are coronary artery disease and nephropathy as a result of hyperglycemia-induced vascular disease.3 Much is known about effects of insulin deficiency, however, little is known about the signaling defects that contribute to the pancreatic autoimmunity seen in the T1DM. Studies in the NOD (non-obese diabetogenic) mice model have found that defects in IL-2 receptor (IL-2R) expression and signaling by T lymphocytes is associated with alteration of their degree of activity and acceleration of disease onset.4 Others found that with disease progression, lymphocytes such as NK cells and autoimmune CD4+ T cells show more affinity for IL-2 than Treg cells in diabetic mice.5,6 Taken together, these studies suggest a role for IL-2 in the development of T1DM. Methods. In one experiment, a transgene (IL-2RβY3) was introduced to create a strain of NOD mice (NOD-Y3) with defective IL-2 receptors. Diabetes onset was followed in male and female NOD and NOD-Y3 mice for up to 40 weeks of age. CD4+, CD8+ and Treg cells were isolated from the spleens peripheral lymph nodes, and pancreases of NOD and NOD-Y3 mice. IL-2 signaling of lymphocytes was measured through STAT5 phosphorylation. In the other, CD25 (IL-2 receptor) levels on islet-specific Tregs and conventional T cells were measured in the peripheral blood of NOD mice several times before the onset of diabetes. Similarly, CD25 expression on Treg and conventional T cells in diabetic mice was measured at different points in the progression of the disease. Results. NOD-Y3 mice were found to have fewer regulatory T cells in the pancreas than NOD mice. Also, Y3 mice were found to faster disease onset, decreased amounts of resting Treg and increased amounts of less activated effector Treg cells.4 With disease progression, islet-specific Treg cells of NOD mice showed decreased CD25 expression, and autoreactive conventional T cells showed increased CD25 levels.6 Conclusions. Multiple studies have suggested defective IL-2 signaling as a possible cause of T1DM pathogenesis and progression. This defect can be attributed to dysfunction of multiple immune cells such as Treg, conventional T cells, or NK cells. While it may appear promising, supplemental IL-2 could potentially have untoward effects on autoimmune cells and limits its effectiveness as a potential T1DM therapy.
- Regnell SE, Lernmark A. Early prediction of autoimmune (type 1) diabetes. Diabetologia 2017; 60(8):1370-1381.
- Hamman RF, Bell RA, Dabelea D, et al. The SEARCH for Diabetes in Youth Study: Rationale, Findings, and Future Directions. Diabetes Care 2014; 37(12):3336-3344.
- Barret EJ, Liu Z, King GL, et al. Diabetic Microvascular Disease: An Endocrine Society Scientific Statement. J. Clinical Endocrinology and Metabolism 2017; 102(12):4343-4410.
- Dwyer CJ, Bayer AL, Fotino C, et al. Altered homeostasis and development of regulatory T cell subsets represent an IL-2R-dependent risk for diabetes in NOD mice. Science Signaling 2017; 10(510).
- Sitrin J, Ring A, Garcia KC, Benoist C, Mathis D. Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. Journal of Experimental Medicine 2013; 210(6): 1153-1165.
- Hotta-Iwamura C, Benck C, Coley WD, et al. Low CD25 on autoreactive Tregs impairs tolerance via low dose IL-2 and antigen delivery. Journal of Autoimmunity 2018; 17(1-10).