Recently, the effects of IL-2 during acute infection have been further refined through analysis of the role of this cytokine in the various stages of CD8+ T-cell differentiation. After their initial activation and induction of CD25 expression, a subpopulation of CD8+ T-cells decrease CD25 levels and become unresponsive to further IL-2 signals, and, at the same time, upregulate the IL-7Rα-chain and develop into long-lived memory cells. This is in contrast to T-cells that are exposed to IL-2 for a prolonged period and maintain CD25 expression, undergo enhanced expansion, but differentiate into short-lived effector cells (SLEC) that are prone to apoptosis and severe population contraction after the peak of the response (Kalia et al., 2010; Obar et al., 2010; Pipkin et al., 2010). The recent development of genetic models allowing the specific depletion of Foxp3+ Treg (Kim et al., 2007; Lahl et al., 2007) without blocking IL-2/CD25 interactions (Murakami et al., 2002; Suvas et al., 2003; Toka et al., 2004; Heit et al., 2008) enabled asking whether Treg differentially affect these CD8+ T-cell subpopulations. Indeed, manipulating the numbers of activated Treg in vivo impacted CD25 expression on activated CD8+ T-cells, indicative of altered IL-2 availability. This resulted in specific changes in numbers of SLEC while leaving the memory CD8+ T-cell compartment largely unaltered (Kastenmuller et al., 2011; McNally et al., 2011). Interestingly, the “window of opportunity” for the regulation of CD8+ T-cell responses by Treg overlapped with the time of CD25 expression on CD8+ T-cells: depletion of Treg cells as late as d2–3 post infection enhanced antigen-specific T-cell numbers in a viral infection model, but depletion later than d5 (when CD8+ T-cells do not express CD25) failed to do so (Kastenmuller et al., 2011). In addition, enhanced expansion of SLEC in the absence of Treg was abrogated through the neutralization of IL-2 (McNally et al., 2011). Therefore, by controlling the availability of IL-2, Treg cells can act as rheostats that balance the differentiation and expansion of pathogen-specific CD8+ effector T-cells. Importantly, by selectively regulating SLEC over memory precursor T-cells, which rapidly seem to become independent of IL-2 signals (d2–3), Treg can limit the extent of acute effector responses of surface CTLA-4 on their surface and this molecule can directly block co-stimulatory molecules and CD28-CD80/86-interactions, or, via trans endocytosis, modulate the amount of CD80/86 that is displayed by DC (Wing et al., 2008; Qureshi et al., 2011). Importantly, the amount of CTLA-4 expressed on Treg is again regulated by IL-2 signals. Consequently, Treg control the level of co-stimulation through CD80/CD86 surface expression not only during steady-state (Schildknecht et al., 2010), but, importantly, also during highly inflammatory processes such as viral infection (Kastenmuller et al., 2011).

Therefore, DC appear to constitute a platform on which both stimulation and regulation of conventional T-cells is executed, with IL-2 being a central mediator that activates both Teff and Treg. Feed-back loops involving the constitutive high levels of CD25 on Tregs and the IL-2-promoted upregulation of CTLA-4 on these cells operate in concert to restrict IL-2 availability to activated Teff, controlling their expansion, differentiation, and survival (Figure 1).