IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation

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Interleukin-2 (IL-2) is a pleiotropic cytokine that drives T-cell growth, augments NK cytolytic activity, induces the differentiation of regulatory T cells, and mediates activation-induced cell death. Along with IL-4, IL-7, IL-9, IL-15, and IL-21, IL-2 shares the common cytokine receptor γ chain, γc, which is mutated in humans with X-linked severe combined immunodeficiency. Herein, we primarily focus on the recently discovered complex roles of IL-2 in broadly modulating T cells for T helper cell differentiation. IL-2 does not specify the type of Th differentiation that occurs; instead, IL-2 modulates expression of receptors for other cytokines and transcription factors, thereby either promoting or inhibiting cytokine cascades that correlate with each Th differentiation state. In this fashion, IL-2 can prime and potentially maintain Th1 and Th2 differentiation as well as expand such populations of cells, whereas it inhibits Th17 differentiation but also can expand Th17 cells.

Highlights

► We examined the role of IL-2 in T helper cell differentiation. ► IL-2 induces its own receptor chains, IL-2Rα and IL-2Rβ. ► Additionally, IL-2 induces IL-4Rα and IL-12Rβ2. ► Conversely, IL-2 represses not only IL-7Rα, but also IL-6Rα and gp130. ► IL-2 thereby promotes Th1 and Th2 but inhibits Th17 differentiation.

Section snippets

IL-2 broadly modulates cytokine receptor expression

IL-2 is well known to induce expression of both IL-2Rα [27] and IL-2Rβ [28], presumably serving as a positive feedback loop, a strategy utilized by other cytokines as well, such as IL-4, IL-12, and IL-21, which also induce expression of their own receptors [29, 30, 31]. More recently, we observed that IL-2 also regulates expression of receptors for heterologous cytokine receptors, inducing IL-4Rα [32••] and IL-12Rβ2 [33••] while repressing IL-6Rα, gp130 [33••], as well as IL-7Rα [34••] (Figure 3

IL-2 and Th2 differentiation

As noted above, IL-4/STAT6 and GATA3 promote differentiation into Th2 cells, which produce IL-4, IL-5, and IL-13 and participate in controlling humoral immunity to extracellular parasites and allergic inflammatory responses [18, 22, 35]. It was recognized that the presence of IL-2 during the Th2 differentiation process is also important [36], with IL-2 opening chromatin accessibility at the Il4 locus in a STAT5A-dependent fashion [37••]. IL-4Rα is not expressed by naïve T cells and thus must be

IL-2 and Th1 differentiation

As noted above, Th1 cells secrete IFNγ to promote the eradication of intracellular pathogens [21, 22]. IL-12 via its activation of STAT4 has been established as the key signal for Th1 differentiation, inducing epigenetic changes at the Ifng locus and enhancing IFNγ expression [38]. IL-12 also induces expression of T-bet [39], a master regulator of Th1 differentiation that induces a transcriptionally permissive chromatin structure at the Ifng locus and enhances IL-12Rβ2 expression [40, 41].

IL-2 and Th17 differentiation

In vitro differentiation of Th17 cells is mediated by IL-6 plus TGF-β [19, 20]; anti-IFNγ and anti-IL-4 are typically added to block Th1 and Th2 differentiation. Interestingly, IL-2 signaling can diminish Th17 cell generation [47••]. Because IL-6 signals via STAT3 and IL-2 via STAT5, it was proposed that IL-2-induced STAT5 competed for STAT3 binding sites in the Il17a gene locus, inhibiting Il17a transcription [48], although direct inhibition of Il17a transcription by STAT5 was not shown. Two

IL-2 and Treg differentiation

Treg cells suppress activation of the immune system and maintain immune homeostasis and tolerance to self-antigens. They include natural Treg (nTreg) and induced Treg (iTreg) cells, which are induced from naïve T cells by TCR stimulation in the presence of TGF-β plus IL-2 [51]. Both types of Treg cells express the Foxp3 transcription factor and IL-2Rα (CD25) [52], and IL-2 is required for their normal development [51]. Consistent with this, Il2, Il2ra, or Il2rb deficient mice exhibit severe

IL-2 and effector/memory cytolytic T cell differentiation

In addition to its actions on CD4+ cells, IL-2 also promotes the development of naïve CD8+ T cells into effector or memory cytolytic T lymphocytes (CTL) depending on the IL-2/IL-2R signal strength [24•, 25•], and IL-2 is crucial for the secondary expansion of memory CD8+ T cells [26]. During viral infection, CD25low cells, which are less sensitive to IL-2, upregulate CD127 and CD62L and give rise to long-lived memory cells, whereas CD25hi cells proliferate more strongly to IL-2, are prone to

Conclusions

IL-2 is a pleiotropic cytokine first identified as a T-cell growth factor that was subsequently shown to have a broad range of other actions as well. IL-2 is now recognized as also important for activation-induced cell death, development of Treg cells, and development of cytotoxic T lymphocytes, as well as for secondary expansion of memory CD8+ T cells, and as detailed herein, for modulating T helper cell differentiation. It is striking that in addition to upregulating IL-2Rα and IL-2Rβ, IL-2

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. We thank Dr. Rosanne Spolski, NHLBI, for critical comments.

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