Reviews and feature article
IL-2– and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets

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IL-2 plays a pivotal role in regulating the adaptive immune system by controlling the survival and proliferation of regulatory T (Treg) cells, which are required for the maintenance of immune tolerance. Moreover, IL-2 is implicated in the differentiation and homeostasis of effector T-cell subsets, including TH1, TH2, TH17, and memory CD8+ T cells. The IL-2 receptor is composed of 3 distinct subunits, namely the α (CD25), β (CD122), and γ (γc) chains. Of crucial importance for the delivery of IL-2 signals to Treg cells is the expression of CD25, which, along with CD122 and γc, confers high affinity binding to IL-2. Notably, recent findings suggest a novel role for CD25, whereby CD25 molecules on Treg cells and possibly other cells are capable of influencing T-cell homeostasis by means of IL-2 deprivation. This review explores these findings and integrates them into our current understanding of T-cell homeostasis.

Section snippets

CD8+ T cells

On activation through signals delivered by the T-cell receptor (TCR) and costimulatory molecules, CD8+ T cells upregulate CD25 and CD122 and become highly IL-2 sensitive. This was a well-known fact by the time IL-2−/− and IL-2R−/− mice became available, and thus the primary response was extensively investigated in these murine models. Interestingly, most studies examining directly primary responses in these knockout animals concluded that IL-2 signaling was not required to generate protective

TH1 and TH2 cells

CD4+ TH cells coordinate immune responses by producing a range of cytokines and are divided into different effector cell subsets based on the functional profiles and cytokines produced. TH1 cells typically produce large amounts of IFN-γ and IL-2, and other proinflammatory cytokines, such as TNF-α, induce immune responses against intracellular pathogens and have been associated with organ-specific autoimmune disorders. In contrast, the signature cytokines of TH2 cells are IL-4, IL-5, and IL-13,

TH17 cells

Recent studies have identified a novel IL-17–producing effector CD4+ population, which is commonly referred to as TH17. This distinct TH subset is believed to be involved in defense against certain extracellular bacteria and some fungi, promotes neutrophilic tissue inflammation, and has been linked to the pathology of chronic inflammatory and autoimmune disorders, such as Crohn disease and psoriasis.27 Little is known about the mechanisms guiding TH17 homeostasis, but the opposing physiologic

Treg cells and immune tolerance

As mentioned previously, mice lacking IL-2 or one of its receptor subunits have a lethal T cell–mediated inflammatory autoimmune disease along with hyperreactivity to commensal bacteria.1 Similar clinical manifestations also accompany CD25 mutation in human subjects, in whom lymphadenopathy and hepatosplenomegaly, along with dense lymphocytic infiltration of tissue and increased susceptibility to viral, fungal, and bacterial infections, are observed.31 Moreover, use of a neutralizing anti–IL-2

Cytokine deprivation: a novel mechanism of action for Treg cells?

Mice lacking CD25 exhibit increased levels of IL-2 in the serum, presumably because of their inability to efficiently bind and use the cytokine through the high-affinity receptor. In turn, these increased serum levels of IL-2 induced vigorous proliferation of adoptively transferred naive CD8+ T cells and their differentiation into memory CD8+ T cells.18 Recent evidence suggests that these observations might be linked to a lack of IL-2 “scavenging” or deprivation by Treg cells.

First, adoptive

Conclusion

IL-2 exerts apparently contradictory functions, promoting proliferation, differentiation, and function of activated CD4+ and CD8+ T cells while inducing activation-induced cell death of CD4+ T cells and mediating the survival of Treg cells. Increasing evidence now suggests a key role for IL-2 in maintaining the balance between protection from pathogens and suppression of self-reactive T cells by providing a powerful negative feedback loop to immune responses. Tight regulation of IL-2 signal

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    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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