Autoreactive T cells display altered CD25 expression that changes responses to low dose IL-2 and antigen delivery.

Abstract

Abstract Dendritic cells (DCs) are important for T cell tolerance induction and treatment of autoimmune diseases such as type 1 diabetes. Chimeric antibodies that deliver self-antigens to DCIR2+ DCs can delay but not completely prevent diabetes development in non-obese diabetic (NOD) mice. These DCIR2 antibodies induce T cell tolerance via antigen-specific deletion and anergy, but do not increase antigen-specific Foxp3+ regulatory T cells (Tregs). Because low dose (LD) IL-2 administration can preferentially expand Tregs, we asked if delivering antigens to tolerogenic DCIR2+ DCs along with IL-2 would boost antigen-specific Tregs and block autoimmunity. But, surprisingly, adding IL-2 did not increase efficacy of DC-targeted antigens to inhibit diabetes. To date, the effect of LD-IL-2 on autoreactive Treg and effector T cells has not been fully elucidated. By using tetramer staining to identify islet-specific CD4+ T cells in NOD mice, we now show the effects of LD-IL-2, with or without specific antigen delivery to DCIR2+ DCs, on both polyclonal and autoreactive effector and regulatory T cells. As expected, LD-IL-2 increased total Tregs, but autoreactive Tregs required addition of antigen and LD-IL-2 to elicit significant expansion. We found that islet-specific Tregs had lower CD25 expression compared to polyclonal Tregs, but islet-specific Foxp3− cells had higher CD25 expression. IL-2 increased activation and expansion of Foxp3− cells, and this effect was more pronounced for autoreactive cells after treatment with IL-2 + islet antigens. Therefore, IL-2, especially when combined with self-antigens, may not be an effective treatment for chronic autoimmunity, and increased Foxp3+ cells may not be a good biomarker for treatment efficacy.