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

Abstract

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, γ(c), 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.

Figure 1

γ_c-family cytokines. Shown are the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These cytokines each activate STAT proteins through phosphorylation of JAK1 and JAK3. The principal STAT protein activated by each cytokine is in bold. DC, dendritic cell; NK cell, natural killer cell; NKT cell, natural killer T cell. STAT5 refers collectively to STAT5A and STAT5B, which are closely-related tandem head-to-head genes.

Figure 2

IL-2 signals by activating three principal signaling pathways, the SHC/RAS/MAP kinase pathway, JAK1/JAK3/STAT5 pathway, and PI 3-K/AKT/p70 S6 kinase pathway.

Figure 3

Pleiotropic actions of IL-2 on CD4⁺ T cell differentiation via its modulation of cytokine receptor expression. IL-2 modulates effector cell differentiation at least in part via regulation of cytokine receptor expression. It promotes Th1 differentiation by inducing IL-12Rβ2 (and IL-12Rβ1), promotes Th2 differentiation by inducing IL-4Rα, inhibits Th17 differentiation by inhibiting gp130 (and IL-6Rα), and drives Treg differentiation by inducing IL-2Rα. IL-2 also potently represses IL-7Rα, which decreases survival signals that normally promote cell survival and memory cell development.