Much data support an essential role for interleukin (IL)-2 in immune tolerance. This idea is much different from the early paradigm in which IL-2 is central for protective immune responses. This change in thinking occurred when a T regulatory cell defect was shown to be responsible for the lethal autoimmunity associated with IL-2/IL-2R deficiency. This realization allowed investigators to explore immune responses in IL-2-nonresponsive mice rendered autoimmune-free. Such studies established that IL-2 sometimes contributes to optimal primary immune responses, but it is not mandatory. Emerging findings, however, suggest an essential role for IL-2 in immune memory. Here, the current understanding of the dual role of IL-2 in maintaining tolerance and contributing to immunity in vivo is reviewed with some emphasis on T regulatory cell production and homeostasis. Also discussed are implications of this new appreciation concerning the immunobiology of IL-2 with respect to targeting IL-2 or its receptor in immunotherapy.

Lethal autoimmunity associated with IL-2Rbeta-deficient mice is prevented after thymic transgenic expression of wild-type IL-2Rbeta in IL-2Rbeta(-/-) mice (Tg -/- mice). Here, we show that CD4(+)CD25(+) regulatory T cells were not readily detected in IL-2Rbeta(-/-) mice, but the production of functional CD4(+)CD25(+) T cells was reconstituted in Tg -/- mice. Adoptive transfer of normal CD4(+)CD25(+) T cells into neonatal IL-2Rbeta-deficient mice prevented this lethal autoimmune syndrome. The CD4(+)CD25(+) T cells in disease-free adult IL-2Rbeta-deficient recipient mice were present at a near normal frequency, were solely donor-derived, and depended on IL-2 for expansion. These observations indicate that the essential function of the IL-2/IL-2R system primarily lies at the level of the production of CD4(+)CD25(+) regulatory T cells.

Interleukin-2 receptor (IL-2R) signaling regulates tolerance and immunity. Here, we review recent work concerning the structure, signaling, and function of the IL-2R, emphasizing the contribution of IL-2 for T cell-dependent activity in vivo. IL-2R signaling influences two discrete aspects of immune responses by CD8+ T cells, terminal differentiation of effector cells in primary responses, and aspects of memory recall responses. IL-2 also delivers essential signals for thymic development of regulatory T (Treg) cells and later to promote their homeostasis and function. Each of these outcomes on T effector and Treg cells requires distinct amounts of IL-2R signaling, with low IL-2R signaling sufficient for many key aspects of Treg cells. Thus, tolerance is readily maintained and favored with limited IL-2.

Interleukin-2 (IL-2) was identified based on its potent T-cell growth-factor activity and is widely considered to be a key cytokine in T-cell-dependent immune responses. However, the main non-redundant activity of this cytokine centres on the regulation of T-cell tolerance, and recent studies indicate that a failure in the production of CD4(+)CD25(+) regulatory T cells is the underlying cause of autoimmunity in the absence of IL-2. In marked contrast to the importance of IL-2 in peripheral T-cell tolerance, T-cell immunity is readily elicited to various agents in the absence of IL-2 in vivo. Here, we discuss these findings and, in particular, the action of IL-2 on regulatory T cells and effector cells, and the targeting of IL-2 and/or the IL-2 receptor in clinical settings.

IL-21 costimulates B cell proliferation and cooperatively with IL-4 promotes T cell-dependent Ab responses. Somewhat paradoxically, IL-21 also induces apoptosis of B cells. The present study was undertaken to more precisely define the expression of the IL-21R, using a novel mAb, and the circumstances by which IL-21 promotes B cell growth vs death. The IL-21R was first detected during T and B cell development, such that this receptor is expressed by all mature lymphocytes. The IL-21R was further up-regulated after B and T activation, with the highest expression by activated B cells. Functional studies demonstrated that IL-21 substantially inhibited proliferation and induced Bim-dependent apoptosis for LPS or CpG DNA-activated B cells. In contrast, IL-21 induced both costimulation and apoptosis for anti-CD40-stimulated B cells, whereas IL-21 primarily costimulated B cells activated by anti-IgM or anti-IgM plus anti-CD40. Upon blocking apoptosis using C57BL/6 Bim-deficient or Bcl-2 transgenic B cells, IL-21 readily costimulated responses to anti-CD40 while proliferation to LPS was still inhibited. Engagement of CD40 or the BCR plus CD40 prevented the inhibitory effect by IL-21 for LPS-activated B cells. Collectively, these data indicate that there are three separable outcomes for IL-21-stimulated B cells: apoptosis, growth arrest, or costimulation. We favor a model in which IL-21 promotes B cell maturation during a productive T cell-dependent B cell response, while favoring growth arrest and apoptosis for nonspecifically or inappropriately activated B cells.