The effect of regulatory T-cell depletion on the spectrum of organ-specific autoimmune diseases in nonobese diabetic mice at different ages

Abstract

The non-obese diabetic (NOD) mouse spontaneously develops several autoimmune diseases, including type 1 diabetes and to a lesser extent thyroiditis and sialitis. Imbalance between effector T cells (Teffs) and regulatory T cells (Tregs) has recently been proposed as a mechanism for the disease pathogenesis in NOD mice, but previous studies have shown the various outcomes by different timing and methods of Treg-depletion. This study was therefore designed to compare the consequences of Treg-depletion by the same method (anti-CD25 antibody) on the spectrum of organ-specific autoimmune diseases in NOD mice of different ages. Treg-depletion by anti-CD25 antibody at 10 days of age accelerated development of all three diseases we examined (insulitis/diabetes, thyroiditis and sialitis); Treg-depletion at 4 weeks of age accelerated only diabetes but not thyroiditis or sialitis; and Treg-depletion at 12 weeks of age hastened only development of thyroiditis and exhibited little influence on diabetes or sialitis. Increased levels of insulin autoantibodies (IAA) were however observed in mice depleted of Tregs at 10 days of age, not in those at 4 weeks. Thus, the consequences of Treg-depletion on the spectrum of organ-specific autoimmune diseases depend on the timing of anti-CD25 antibody injection in NOD mice. Aging gradually tips balance between Teffs and Tregs toward Teff-dominance for diabetes, but this balance for thyroiditis and sialitis likely alters more intricately. Our data also suggest that the levels of IAA are not necessarily correlated with diabetes development.

The Immune System in the Elderly: A Fair Fight Against Diseases?

“…This reduced cytotoxic T-lymphocyte antigen-4 expression may induce lower inhibition of T-cell activation and proliferation that may explain the loss of b cell and the development of fulminant Type 1 diabetes [66]. It has been reported that aged nonobese diabetic mice, which develops Type 1 diabetes, gradually switch the balance between effector T cells and Tregs toward effector T-cell dominance for diabetes [67]. Altogether, this suggests that although lifestyle may be a dominant factor for the development of diabetes, the aging of the immune system may sustain such events.…”

Thymic Development of Autoreactive T Cells in NOD Mice Is Regulated in an Age-Dependent Manner

“…Aberrant survival of islet resident Foxp3-expressing immunoregulatory CD4 + T cells (Foxp3 + Treg) is then believed to promote a wave of robust β cell destruction and the onset of overt diabetes (26, 27). NOD mice also exhibit T cell autoimmunity to other tissues such as the thyroid (28, 29) and salivary gland (30), and low levels of colitis (31, 32) are detected suggesting general defects in mechanisms regulating autoimmune and inflammatory responses, respectively.…”

Unmasking of autoreactive CD4 T cells by depletion of CD25 regulatory T cells in systemic lupus erythematosus

“…In addition, naturally occurring Treg that lack CD25 expression have been reported 26. However, to eliminate the majority of Treg effectively CD25 depletion is still a practical approach 26 27. This is further underlined by our recent studies showing that CD25 depletion effectively aggravates disease progression in lupus mice,16 and that the majority of peripheral CD25 + T cells in our SLE patients is characterised by a Treg-like FoxP3 + CD127 – phenotype (unpublished observations).…”