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Review
. 2020 Jan 6;217(1):e20191247.
doi: 10.1084/jem.20191247.

Effects of interleukin-2 in immunostimulation and immunosuppression

Jonathan G Pol  1   2   3   4   5 , Pamela Caudana  6 , Juliette Paillet  1   2   3   4   5   7 , Eliane Piaggio  6   8 , Guido Kroemer  1   2   3   4   5   9   10   11
Affiliations
Review

Effects of interleukin-2 in immunostimulation and immunosuppression

Jonathan G Pol et al. J Exp Med. .

Abstract

Historically, interleukin-2 (IL-2) was first described as an immunostimulatory factor that supports the expansion of activated effector T cells. A layer of sophistication arose when regulatory CD4+ T lymphocytes (Tregs) were shown to require IL-2 for their development, homeostasis, and immunosuppressive functions. Fundamental distinctions in the nature and spatiotemporal expression patterns of IL-2 receptor subunits on naive/memory/effector T cells versus Tregs are now being exploited to manipulate the immunomodulatory effects of IL-2 for therapeutic purposes. Although high-dose IL-2 administration has yielded discrete clinical responses, low-dose IL-2 as well as innovative strategies based on IL-2 derivatives, including "muteins," immunocomplexes, and immunocytokines, are being explored to therapeutically enhance or inhibit the immune response.

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Figures

Figure 1.
Figure 1.
IL-2 transcription following stimulation of the TCR and CD28 signaling cascades. Interactions between the CD4 (or CD8)/TCR complex at the surface of a T lymphocyte and an MHC-II (or MHC-I) molecule coupled to a cognate antigen at the surface of an APC triggers several intracellular signaling pathways leading to IL-2 production. Precisely, upon CD4/CD8 binding to MHC, lymphocyte-specific protein tyrosine kinase (Lck) is carried to the TCR proximity and is autophosphorylated and activated. Lck can phosphorylate CD3, which recruits the protein zeta-chain–associated protein kinase 70 (ZAP-70). ZAP-70 undergoes trans-autophosphorylation, leading to its activation, and phosphorylates the linker for the activation of T cells (LAT). Then, LAT plays as an adaptor protein supplying docking sites for: (i) growth factor receptor-bound protein 2 (GRB2); (ii) GRB2-related adaptor protein 2 (also known as GADS); and (iii) phospholipase C gamma1 (PLCγ). GRB2 binds to the son of sevenless protein (SOS), which activates Ras guanyl-releasing protein 1 (RasGRP1). RasGRP1 promotes the release of guanosine diphosphate (GDP) and the binding of guanosine triphosphate (GTP) on membrane-associated protein Ras, a small GTPase. GTP-bound Ras recruits the rapidly accelerated fibrosarcoma protein (Raf) and promotes its dimerization and activation by autophosphorylation. Activated Raf recruits and phosphorylates the mitogen-activated protein kinase kinases 1 and 2 (best known as MEK1/2), which in turn phosphorylate ERK1/2. Phosphorylated ERK1/2 translocates to the nucleus and activates ETS Like-1 protein (Elk1), mitogen and stress activated protein kinases 1 and 2 (MSK1/2), and p90 ribosomal S6 kinases (RSKs). The transcription factor Elk1, together with RSKs, promotes the expression of the gene FOS, while MSK1/2 activates c-AMP response element-binding protein (CREB). RSKs also phosphorylate JUN, enhancing the transcriptional activity of AP-1, which is constituted of a heterodimer of JUN and FOS. Both AP-1 and CREB translocate to the nucleus, bind to promoter of the IL2 gene, and stimulate its transcription. SH2 domain containing leukocyte protein of 76 kD (SLP-76) is recruited to GADS and phosphorylated by ZAP-70. Phosphorylated SLP-76 recruits PLCγ, the noncatalytic region of tyrosine kinase (NCK) adaptor protein, and the proteins Vav and interleukin-2-inducible T cell kinase (ITK). Fyn phosphorylates Vav, a guanine nucleotide exchange factor, which can activate Ras-related C3 botulinum toxin substrate 1 (Rac1), cell division control protein 42 homologue (Cdc42), and Ras homologue gene family, member A (RhoA), which are involved in cytoskeleton rearrangement. NCK recruits the p21-activated serine/threonine kinase (PAK) at the membrane, and the Cdc42/Rac1 complex activates PAK by disrupting PAK homodimerization and allowing its autophosphorylation. This leads to the activation of mitogen-activated protein kinase kinase kinase 1 (MEKK1) and dual specificity mitogen-activated protein kinase kinases (MKKs) 3 and 6 (MKK3/6). MEKK1 can further phosphorylate MKK4/7, and activated MKK4/7 activates in turn JNKs. Then, JNKs phosphorylate JUN leading to an enhanced transcriptional activity of the AP-1 complex. JNKs also activate the activating transcription factor 2 (ATF2) that phosphorylates and promotes the transcription of JUN. MKK3/6 phosphorylates P38 mitogen-activated kinases, which further activate ATF2 and MSK1/2. The recruitment of PLCγ by SLP-76 leads to its phosphorylation by ITK and ZAP-70. PLCγ detaches from SLP-76, re-translocates to the plasma membrane, binds to phosphatidylinositol 4,5-bisphosphate (PIP2), and hydrolyses PIP2 to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). IP3 binds to its receptor, IP3 receptor (IP3R), leading to the release of Ca2+ from ER, which activates calmodulin (CaM). This cytosolic influx of Ca2+ from ER stores ignites a prolonged opening of Ca2+ release–activated Ca2+ channels (CRAC) located at the plasma membrane, a requirement for sustaining T cell functions. Then, CaM binds to calcineurin (CaN), leading to its activation. CaN dephosphorylates NFAT, which can translocate into the nucleus. In the meantime, DAG can recruit to the plasma membrane and activate RasGRP1, leading to the downstream signaling pathway of Ras/Raf. Additionally, DAG also recruits the protein kinase C theta (PKCθ), leading to a conformational change and its phosphorylation by Lck. Simultaneously, the 3-phosphoinositide-dependent protein kinase 1 (PDPK1) is translocated to the membrane by binding to PIP2 or PIP3. Then, PDPK1 binds to caspase recruitment domain-containing protein 11 (CARMA1) and phosphorylates PKCθ; the latter autophosphorylates to achieve full activation. PKCθ phosphorylates CARMA1, which undergoes oligomerization and recruits BCL10. Afterwards, BCL10 oligomerizes and is phosphorylated by the receptor-interacting serine/threonine-protein kinase 2, leading to the recruitment of the mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MATL1). In turn, MATL1 oligomerizes and binds to the TNF receptor-associated factor 6 (TRAF6). Then follows TRAF6 oligomerization, activation of its ubiquitin ligase activity, and auto-polyubiquitination. Ubiquitinated TRAF6 recruits the mitogen-activated protein kinase kinase kinase 7-interacting protein 2 (TAB2), which binds the mitogen-activated protein kinase kinase kinase 7 (best known as the transforming growth factor β-activated kinase 1 [TAK1]). The complex TAB2/TAK1 is ubiquitinated by TRAF6, and TAK1 undergoes autophosphorylation. Then, TAK1 phosphorylates MKK7, which activates JNK2. Then follows the JNK2-mediated phosphorylation of JUN, which associates with FOS to form the AP-1 complex. Activated TAK1 also phosphorylates NFκB inhibitor kinase subunit β (IKKβ), while TRAF6 ubiquitinates the γ subunit IKKγ (also known as NFκB essential modifier). Simultaneously, PDPK1 phosphorylates PKB (best known as AKT), allowing the latter to activate the mitogen-activated protein kinase kinase kinase 8 (also known as cancer osaka thyroid oncogene [COT]). COT activates the NFκB-inducing kinase (NIK, also known as MAP3K14), which phosphorylates IKKα. It results in an activated IKK complex composed of IKKα/β/γ. The NFκB inhibitor α (best known as IκBα), which otherwise sequesters the transcription factor NFκB in the cytoplasm, is phosphorylated by the IKK complex and then undergoes ubiquitination and degradation. The released NFκB, a heterodimer constituted of p50 (also known as NFκB subunit 1) and p65 (also known as v-Rel avian reticuloendotheliosis viral oncogene homologue A [RELA]), can therefore translocate to the nucleus. Ultimately, together with constitutive transcription factors like the octamer-binding protein 1 (OCT1, also known as POU domain class 2 transcription factor 1), the nuclear translocation of AP-1, NFκB, NFAT, and CREB, which all dispose of cis-regulatory elements within the promoter of the IL2 gene, will initiate its transcription. Moreover, AKT phosphorylates mTOR within the mTORC1 complex, composed of Raptor, proline-rich AKT substrate of 40 kD, DEP domain-containing mTOR-interacting protein, and mammalian lethal with SEC13 protein 8. mTORC1 can phosphorylate the eukaryotic translation initiation factor (eIF) 4E-binding protein 1 (4E-BP1), thus abrogating its inhibitory sequestration of eIF4E. mTORC1 also activates the ribosomal protein S6 kinase β-1 (S6K1). S6K1 phosphorylates and activates thereafter the ribosomal protein s6 as well as the translation initiation factors eIF4B and eIF4G, while inactivating eIF2K by phosphorylation. Altogether, these events up-regulate mRNA translation. Concurrent with the activation of the TCR signaling, a co-stimulatory signal, consecutive to the interaction of B7-1 (CD80) or B7-2 (CD86) on an APC with CD28 on the T cell, is triggered. The intracellular downstream signaling pathway starts with the phosphorylation of CD28 by Lck and Fyn, allowing the recruitment to CD28 of PI3Ks, GRB2, and GADS. PI3K can further phosphorylate PIP2 to PIP3, leading to the recruitment of PDPK1 and AKT to the membrane. The resulting stimulation of the AKT downstream signaling pathway activates NFκB and promotes the up-regulation of mRNA translation by mTORC1. In the meantime, Vav is recruited to the membrane through binding to GRB2 or PIP3 and phosphorylated by Fyn. Thereafter, Vav can stimulate Rac1, Cdc42, and RhoA-related cytoplasmic events. Sources: Reactome; KEGG pathway (Huse, 2009; Courtney et al., 2018).
Figure 2.
Figure 2.
IL-2R signaling and modulation of T cell activity. IL-2R is composed of up to three subunits: α (IL2RA), β (IL2RB), and γ (IL2RG). The intermediate-affinity IL-2R is composed of the IL2RB and IL2RG subunits. The high-affinity receptor consists either of the cis gathering of the three subunits, for instance, on a T cell, or of the cis assembly of IL2RB and IL2RG complemented in trans with IL2RA located at the surface of a DC. IL2RB and IL2RG are respectively bound to the JAK1 and JAK3 and responsible for transducing intracellular signaling. Upon ligation of IL-2, JAK3 phosphorylates JAK1, which in turn recruits to IL2RB the spleen-associated tyrosine kinase (SYK) and phosphorylates it. JAK1 also phosphorylates IL2RB, leading to the recruitment of the STAT5A or its paralog STAT5B. STAT5A/B is further phosphorylated by JAK3, but JAK1 could also be involved. Phosphorylated STAT5A/B is then released from IL-2R and dimerizes in the cytosol. The dimer can finally translocate to the nucleus and regulates genes encoding immune-related factors such as IL2RA itself, or again FOXP3, Fas-ligand (FASL), positive regulatory domain zinc finger protein 1 (PRDM1), or suppressor of cytokine signaling 1 or 2 (SOCS1/2). The phosphorylation of IL2RB also creates binding sites for the SHC-transforming protein 1 (SHC1), which is phosphorylated probably by JAK1 or Lck (still unclear). SHC1 then recruits the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1). The SHC1/SHIP1 complex is stabilized through interaction with GRB2, itself associated with GRB2-associated binder 2 (GAB2). SHC1 promotes the phosphorylation of GAB2, but the kinase involved is not clear. Phosphorylated GAB2 can further recruit PI3Ks to the membrane, leading to the activation of the PI3K/PKB (best known as AKT)/mTOR pathway. JAK1 may also recruit PI3K. In the meantime, SHC1 recruits the complex GRB2/SOS. SOS interacts with, and activates, RasGRP1, resulting in the activation of the Ras/Raf pathway and the regulation of genes involved in T cell response. Sources: Reactome; KEGG pathway (Ross and Cantrell, 2018).
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