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.

Although many aspects of CD4+CD25+ T regulatory (Treg) cell development remain largely unknown, signaling through the IL-2R represents one feature for the production of Treg cells. Therefore, the present study was undertaken to further define early developmental steps in the production of Treg cells, including a more precise view on the role of interleukin (IL)-2 in this process. After adoptive transfer of wild-type Treg cells into neonatal IL-2Rβ−/− mice, only a small fraction of donor Treg cells selectively seeded the lymph node (LN). These donor Treg cells underwent rapid and extensive IL-2–dependent proliferation, followed by subsequent trafficking to the spleen. Thus, IL-2 is essential for Treg cell proliferation in neonatal LN. The number and distribution of Treg cells in the periphery of normal neonatal mice closely paralleled that seen for IL-2Rβ−/− mice that received Treg cells. However, for normal neonates, blockade of IL-2 decreased Treg cells in both the thymus and LN. Therefore, two steps of Treg cell development depend upon IL-2 in neonatal mice, thymus production, and subsequent expansion in the LN.

IL-2 contributes to the production, function, and homeostasis of CD4+CD25+ Treg cells. However, it remains uncertain whether IL-2 is essential for the development of Treg cells in the thymus, their homeostasis in the periphery, or both. The present study was undertaken to investigate the contribution of IL-2 during thymic Treg cell development and its maintenance in peripheral immune tissue. Relying on genetic mouse models where IL-2R signaling was either completely blocked or selectively inhibited in peripheral CD4+CD25+ Treg cells, we show that the IL-2/IL-2R interaction is active in the thymus at the earliest stage of the development of Treg cells to promote their expansion and to up-regulate Foxp3 and CD25 to normal levels. Furthermore, CD4+CD25+Foxp3+ Treg cells with impaired IL-2-induced signaling persist in the periphery and control autoimmunity without constant thymic output. These peripheral Treg cells with poor responsiveness to IL-2 exhibited slower growth and extended survival in vivo, somewhat lower suppressive activity, and poor IL-2-dependent survival in vitro. Mixed thymic and bone marrow chimeric mice showed that wild-type-derived Treg cells were substantially more effective in populating peripheral immune tissue than Treg cells with impaired IL-2 signaling. Collectively, these data support the notion that normally IL-2 is a dominant mechanism controlling the number of thymic and peripheral Treg cells.

Intravital imaging emerged as an indispensible tool in biological research, and a variety of imaging techniques have been developed to noninvasively monitor tissues in vivo. However, most of the current techniques lack the resolution to study events at the single-cell level. Although intravital multiphoton microscopy has addressed this limitation, the need for repeated noninvasive access to the same tissue in longitudinal in vivo studies remains largely unmet. We now report on a previously unexplored approach to study immune responses after transplantation of pancreatic islets into the anterior chamber of the mouse eye. This approach enabled ( i ) longitudinal, noninvasive imaging of transplanted tissues in vivo; ( ii ) in vivo cytolabeling to assess cellular phenotype and viability in situ; ( iii ) local intervention by topical application or intraocular injection; and ( iv ) real-time tracking of infiltrating immune cells in the target tissue.

Abstract-Protein kinase C (PKC) ⑀ and PKC␦ translocation in neonatal rat ventricular myocytes (NRVMs) is accompanied by subsequent activation of the ERK, JNK, and p38 MAPK cascades; however, it is not known if either or both novel PKCs are necessary for their downstream activation. Use of PKC inhibitors to answer this question is complicated by a lack of isoenzyme specificity, and the fact that many PKC inhibitors stimulate JNK and p38 MAPK activity. Therefore, replication-defective adenoviruses (Advs) encoding constitutively active (ca) mutants of PKC⑀ and PKC␦ were used to test if either or both of these PKCs are sufficient to activate ERKs, JNKs, and/or p38 MAPK in NRVMs. Adv-caPKC⑀ infection (1 to 25 multiplicities of viral infection (MOI); 4 to 48 hours) increased total PKC⑀ levels in a time-and dose-dependent manner, with maximal expression observed 8 hours after Adv infection. Adv-caPKC⑀ induced a time-and dose-dependent increase in phosphorylated p42 and p44 ERKs, as compared with a control Adv encoding ␤-galactosidase (Adv-ne␤gal). Maximal ERK phosphorylation occurred 8 hours after Adv infection. In contrast, JNK was only minimally activated, and p38MAPK was relatively unaffected. Adv-caPKC␦ infection (1 to 25 MOI, 4 to 48 hours) increased total PKC␦ levels in a similar fashion. Adv-caPKC␦ (5 MOI) induced a 29-fold increase in phosphorylated p54 JNK, and a 15-fold increase in phosphorylated p38MAPK 24 hours after Adv infection. In contrast, p42 and p44 ERK were only minimally activated. Whereas neither Adv induced NRVM hypertrophy, Adv-caPKC␦, but not Adv-caPKC⑀, induced NRVM apoptosis. We conclude that the novel PKCs differentially regulate MAPK cascades and apoptosis in an isoenzyme-specific and time-dependent manner. here is now substantial evidence to indicate a critical role for protein kinase C (PKC) activation in coordinating specific aspects of cardiomyocyte hypertrophy. 1 Previous studies have also implicated PKCs as potential upstream regulators of the mitogen-activated protein kinases (MAPK), which are involved in both hypertrophic signal transduction, 2 as well as apoptosis. 3 However, cardiomyocytes express several PKC isoenzymes that are differentially activated by various stimuli. For instance, the hypertrophic agonists endothelin-1 (ET) and phenylephrine (PE) caused the membrane translocation of PKC⑀, and to a lesser extent PKC␦, in cultured neonatal rat ventricular myocytes (NRVMs). 4,5 ETinduced PKC⑀ and PKC␦ translocation was accompanied by subsequent activation of all three MAPK cascades. [5][6][7][8][9] In contrast, electrical stimulation of contraction induced a similar degree of cardiomyocyte hypertrophy, but predominantly activated PKC␦ rather than PKC⑀. 10 Electrical pacing was also associated with a rapid increase in JNK 10,11 and p38 MAPK 12 activities, but ERKs were not significantly activated. 10,11 None of these hypertrophic stimuli induced the membrane translocation of PKC␣, the major Ca 2ϩ -dependent, phorbol-ester-sensitive PKC in NRVMs. 4,5,10 Although PKC⑀ has been imp...