Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy

Abstract

Interleukin-2 (IL-2) is a pleiotropic cytokine produced after antigen activation that plays pivotal roles in the immune response. Discovered as a T cell growth factor, IL-2 additionally promotes CD8(+) T cell and natural killer cell cytolytic activity and modulates T cell differentiation programs in response to antigen, promoting naïve CD4(+) T cell differentiation into T helper 1 (Th1) and T helper 2 (Th2) cells while inhibiting T helper 17 (Th17) and T follicular helper (Tfh) cell differentiation. Moreover, IL-2 is essential for the development and maintenance of T regulatory cells and for activation-induced cell death, thereby mediating tolerance and limiting inappropriate immune reactions. In this review, we focus on the molecular mechanisms and complex cellular actions of IL-2, its cooperative and opposing effects with other cytokines, and how both promoting and blocking the actions of IL-2 are being utilized in clinical medicine.

Figure 1. The γ_c family of cytokines

Shown are the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, as well as major actions for these cytokines. Crosses in red indicate that mutation of IL2RG gene, which encodes γ_c, results in X-linked severe combined immunodeficiency in humans (XSCID, where both T cells and NK cells are greatly diminished [T⁻B⁺NK⁻ SCID]), mutation of IL2RA results in an autoimmune syndrome, defective expression of IL2RB results in NK-deficient SCID (where T and B cells remain [T⁺B⁺NK⁻ SCID]), and mutation of IL7R causes T-cell selective form of SCID, where B and NK cell numbers are normal (T⁻B⁺NK⁺ SCID). JAK3 is not shown as it interacts with the cytoplasmic domain of γ_c; however, mutations in JAK3, as noted in the text, cause a T⁻B⁺NK⁻ for SCID, like XSCID.

Figure 2. Factors regulating the IL2 (A), IL2RA (B), IL2RB (C), and IL2RG (D) genes

For each gene, the binding locations of transcription factors are shown. For some of these factors, there are only in vitro data that indicate their importance, whereas for others such as STAT5A and STAT5B, extensive in vivo data have established their importance (e.g., of STAT5A and STAT5B for regulation of IL-2Rα expression). (A) Multiple factors, including for example NFAT, AP1, and NF-κB bind to and regulate the IL2 gene. (B) In the IL2RA gene, PRRI binds SP1, SRF, and NF-κB; PRRII binds Elf-1 as well as HMG-I and/or HMG-Y; PRRIII binds STAT5A, STAT5B, ELF1, and GABP, as well as HMG-I and/or HMG-Y, PRRIV binds NFAT, AP1, STAT5A, and STAT5B; PRRV binds SMAD3, AP1, and CREB-ATF factors, and PRRVI binds AP1 and CREB-ATF factors. (C) Factors including ETS1 bind to and regulate the IL2B gene. (D) Only limited information is available regarding the factors regulating IL2RG.

Figure 3. Classes of IL-2 receptors

Shown are the three classes of IL-2 receptors (high-affinity, intermediate affinity, and low affinity), with receptor composition, K_d’s, receptor composition, and associated JAK kinases. Also shown is trans-presentation of IL-2 by a DC that expresses IL-2Rα to a T cell that expresses IL-2Rβ and γ_c. On the right is the soluble IL-2 receptor (soluble IL-2Rα) with bound IL-2. As discussed in the text, IL-2 is produced primarily by activated CD4⁺ T cells.

Figure 4. Schematic of major IL-2 signaling pathways

Shown is the activation of PI 3-K-AKT, JAK-STAT, and SHC-RAS-MAPK signaling pathways. Also shown are potential therapeutic points of control for IL-2 signaling, with anti-Tac (daclizumab), rapamycin, and JAK1 or JAK3 inhibitors being shown in red. The cartoon shows signaling by both STATs dimers and tetramers. The figure indicates that IL-2 activates more STAT5 than STAT3 and more STAT3 than STAT1. ERK refers to both ERK1 and ERK2. MEK refers to both MEK1 and MEK2.

Figure 5. IL-2 is important in many types of T effector cell differentiation

Shown is the induction by IL-2 of IL-12Rβ2 to promote Th1 cell differentiation, of IL-4Rα to promote Th2 cell differentiation, and of IL-2Rα to promote Treg cell differentiation. Conversely, IL-2 represses expression of gp130 (and IL-6Rα) while inducing T-bet (not shown) to repress Th17 cell differentiation. IL-2 is also a repressor of Tfh differentiation based on its repression of BCL6 expression. Finally, IL-2 promotes the differentiation, expansion, and the cytolytic activity of cytotoxic T cells.