Regulatory T cells (T reg cells) play a major role in controlling the pathogenic autoimmune process in type 1 diabetes (T1D). Interleukin 2 (IL-2), a cytokine which promotes T reg cell survival and function, may thus have therapeutic efficacy in T1D. We show that 5 d of low-dose IL-2 administration starting at the time of T1D onset can reverse established disease in NOD (nonobese diabetic) mice, with long-lasting effects. Low-dose IL-2 increases the number of T reg cells in the pancreas and induces expression of T reg cell–associated proteins including Foxp3, CD25, CTLA-4, ICOS (inducible T cell costimulator), and GITR (glucocorticoid-induced TNF receptor) in these cells. Treatment also suppresses interferon γ production by pancreas-infiltrating T cells. Transcriptome analyses show that low-dose IL-2 exerts much greater influence on gene expression of T reg cells than effector T cells (T eff cells), suggesting that nonspecific activation of pathogenic T eff cells is less likely. We provide the first preclinical data showing that low-dose IL-2 can reverse established T1D, suggesting that this treatment merits evaluation in patients with T1D.

Follicular regulatory T (T) cells from lymph node germinal centers control follicular helper T (T) cell-dependent B cell activation. These scarce cells, often described and purified as CD25 cells, are thought to be derived from thymic regulatory T (T) cells. However, we observed that mouse T cells do not respond to interleukin-2 (IL-2), unlike T cells. Stringent immunophenotyping based on B cell lymphoma 6 (Bcl6), programmed cell death protein 1 (PD-1), and CXCR5 expression revealed that T cells are actually CD25, in mice and humans. Moreover, T cell characterization based only on CXCR5 and PD-1 high expression without excluding CD25 cells resulted in contamination with T cells. Transcriptome studies of CD4CXCR5PD-1Bcl6Foxp3CD25 T cells revealed that they express the IL-1 decoy receptor IL-1R2 and the IL-1 receptor antagonist IL-1Ra, whereas T cells express the IL-1R1 agonist receptor. IL-1 treatment expanded T cells in vivo and activated their production of IL-4 and IL-21 in vitro. T cells suppressed the IL-1-induced activation of T cells as efficiently as the IL-1 receptor antagonist Anakinra. Altogether, these results reveal an IL-1 axis in the T cell control of B cell responses and an IL-2/IL-1 dichotomy for T cell control of effector T cells versus T cell control of T cells.

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