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.

The microanatomy of immune clearance of infected brain cells remains poorly understood. Immunological synapses are essential anatomical structures that channel information exchanges between T cell–antigen-presenting cells (APC) during the priming and effector phases of T cells' function, and during natural killer–target cell interactions. The hallmark of immunological synapses established by T cells is the formation of the supramolecular activation clusters (SMACs), in which adhesion molecules such as leukocyte function-associated antigen 1 segregate to the peripheral domain of the immunological synapse (p-SMAC), which surrounds the T cell receptor–rich or central SMAC (c-SMAC). The inability so far to detect SMAC formation in vivo has cast doubts on its functional relevance. Herein, we demonstrate that the in vivo formation of SMAC at immunological synapses between effector CD8⁺ T cells and target cells precedes and mediates clearance of virally infected brain astrocytes.

Despite a growing interest in CD4⁺ CD25⁺ regulatory T cells (T_reg) that play a major role in self-tolerance and immunoregulation, fundamental parameters of the biology and homeostasis of these cells are poorly known. Here, we show that this population is composed of two T_reg subsets that have distinct phenotypes and homeostasis in normal unmanipulated mice. In the steady state, some T_reg remain quiescent and have a long lifespan, in the order of months, whereas the other T_reg are dividing extensively and express multiple activation markers. After adoptive transfer, tissue-specific T_reg rapidly divide and expand preferentially in lymph nodes draining their target self-antigens. These results reveal the existence of a cycling T_reg subset composed of autoreactive T_reg that are continuously activated by tissue self-antigens.

CD4⁺CD25⁺ immunoregulatory T cells play a pivotal role in preventing organ-specific autoimmune diseases and in tolerance induction to allogeneic organ transplants. We investigated whether these cells could also control graft-versus-host disease (GVHD), the main complication after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we show that the few CD4⁺CD25⁺ T cells naturally present in the transplant regulate GVHD because their removal from the graft dramatically accelerates this disease. Furthermore, the addition of freshly isolated CD4⁺CD25⁺ T cells at time of grafting significantly delays or even prevents GVHD. Ex vivo–expanded CD4⁺CD25⁺ regulatory T cells obtained after stimulation by allogeneic recipient-type antigen-presenting cells can also modulate GVHD. Thus, CD4⁺CD25⁺ regulatory T cells represent a new therapeutic tool for controlling GVHD in allogeneic HSCT. More generally, these results outline the tremendous potential of regulatory T cells as therapeutics.