Alternative titles; symbols
HGNC Approved Gene Symbol: IL2
Cytogenetic location: 4q27 Genomic coordinates (GRCh38): 4:122,451,470-122,456,725 (from NCBI)
Interleukin-2 (IL2), formerly referred to as T-cell growth factor, is a powerfully immunoregulatory lymphokine that is produced by lectin- or antigen-activated T cells (Lowenthal et al., 1985; Smith, 1988). It is produced not only by mature T lymphocytes on stimulation but also constitutively by certain T-cell lymphoma cell lines. It is useful in the study of the molecular nature of T-cell differentiation and, like interferons, augments natural killer cell activity.
Taniguchi et al. (1983) cloned the human IL2 gene. Fujita et al. (1983) found that the IL2 gene has a promoter sequence homologous to that of the human gamma interferon gene (IFNG; 147570).
Using a cloned human TCGF gene in somatic cell hybridization studies, Seigel et al. (1984) assigned the TCGF locus to chromosome 4. In situ hybridization narrowed the assignment to 4q26-q28. Evidence was presented to indicate that TCGF and RAF2, a pseudogene of the oncogene RAF1 (164760), is not closely linked to TCGF although it is on chromosome 4. Fiorentino et al. (1989) assigned the Il2 locus to mouse chromosome 3 by Southern analysis of Chinese hamster/mouse somatic cell hybrid cells, and Webb et al. (1990) localized it to bands B-C by in situ hybridization.
Lowenthal et al. (1985) presented evidence that IL2 can act as a growth hormone for both B and T lymphocytes. Thus, IL2 is a better designation than TCGF. See review of Smith (1988). IL2 has a molecular weight of 15,000.
Using fluorescence in situ hybridization and single-cell PCR in cells with different IL2 alleles, Hollander et al. (1998) demonstrated that in mature thymocytes and T cells, IL2 expression is monoallelic. Since IL2 is encoded at a nonimprinted autosomal locus, this result indicated an unusual mechanism for regulating the expression of a single gene.
Memory T cells maintain their numbers for long periods after antigen exposure. Ku et al. (2000) demonstrated that CD8+ T cells of memory phenotype divide slowly in animals. This division requires interleukin-15 (IL15; 600554) and is markedly increased by inhibition of interleukin-2. The authors therefore suggested that the numbers of CD8+ memory T cells in animals are controlled by a balance between IL15 and IL2.
Helicobacter pylori vacuolating cytotoxin VacA induces cellular vacuolation in epithelial cells. Gebert et al. (2003) found that VacA could efficiently block proliferation of T cells by inducing a G1/S cell cycle arrest. VacA interfered with the T cell receptor/IL2 signaling pathway at the level of the calcium-calmodulin-dependent phosphatase calcineurin (see 114105). Nuclear translocation of NFAT (see 600490) was abrogated, resulting in downregulation of IL2 transcription. VacA partially mimicked the activity of the immunosuppressive drug FK506 by possibly inducing a local immune suppression, explaining the extraordinary chronicity of Helicobacter pylori infections.
Ferlazzo et al. (2004) observed that peripheral blood natural killer (NK) cells have a CD56 (NCAM1; 116930)-dim/CD16 (FCGR3A; 146740)-positive phenotype and express perforin (170280), the natural cytotoxicity receptors (NCRs) NKp30 (NCR3; 611550) and NKp46 (NCR1; 604530), and, in part, killer cell Ig-like receptors (KIRs, see 604936). In contrast, lymph node NK cells have mainly a CD56-bright/CD16-negative phenotype and lack perforin, KIRs, and NCRs, except for low levels of NKp46. Tonsilar NK cells also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 (NCR2; 604531) and NKp46. Ferlazzo et al. (2004) found that IL2 stimulation leads lymph node and tonsilar NK cells to upregulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL2 activation and therefore display a phenotype similar to peripheral blood NK cells. Ferlazzo et al. (2004) hypothesized that IL2 can mobilize NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. They also showed that NK cells isolated from lymphoid tissues produce IFNG (147570) after activation by IL2 and IL12 (see 161560). The results suggested that secondary lymphoid organs are possible sites of NK-cell differentiation and self-tolerance acquisition.
Williams et al. (2006) showed that although IL2 signaling to pathogen-specific CD8+ T cells affects the number of developing effector and memory cells very little, it is required for the generation of robust secondary responses. This is not due to an altered T cell receptor repertoire development or selection, and does not reflect an acute requirement for IL2 during secondary activation and expansion. Rather, Williams et al. (2006) demonstrated a previously unappreciated role for IL2 during primary infection in programming the development of CD8+ memory T cells capable of full secondary expansion.
Using an approach that combined the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, Zielinski et al. (2012) described 2 types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL17 (603149) and IFN-gamma but no IL10 (124092), whereas Staphylococcus aureus-specific TH17 cells produced IL17 and could produce IL10 upon restimulation. Zielinski et al. (2012) showed that, after restimulation, TH17 cells transiently downregulated IL17 production through a mechanism that involved IL2-induced activation of STAT5 (601511) and decreased expression of ROR-gamma-t (see 602943). Zielinski et al. (2012) concluded that, taken together, their findings demonstrated that by eliciting different cytokines, C. albicans and S. aureus prime TH17 cells that produce either IFN-gamma or IL10, and identified IL1-beta and IL2 as pro- and antiinflammatory regulators of TH17 cells both at priming and in the effector phase.
Berglund et al. (2013) noted that a feature of autosomal dominant hyper-IgE syndrome (147060) due to STAT3 (102582) deficiency is impaired humoral immunity following infection and vaccination. Using microarray analysis, they analyzed STAT3-deficient and normal human naive B cells after stimulation with CD40L (TNFSF5; 300386) alone or with IL21 (605384). The authors observed upregulation of IL2RA (147730) and IL10 production in normal cells, but not STAT3-deficient cells. IL2 enhanced differentiation of plasma cells and Ig secretion from IL21-stimulated naive B cells. Berglund et al. (2013) concluded that IL21, via STAT3, sensitizes B cells to the stimulatory effects of IL2, which may play an active role in IL21-induced B-cell differentiation.
Smigiel et al. (2014) noted that FOXP3 (300292)-positive regulatory T cells (Tregs) depend on IL2 for maintaining tolerance and preventing autoimmunity. They showed that mouse central Tregs (cTregs), which express low levels of Cd44 (107269) and high levels of Cd62l (SELL; 153240) (i.e., Cd44-lo/Cd62l-hi), were quiescent and long-lived. In contrast, mouse effector Tregs (eTregs), which are Cd44-hi/Cd62l-lo, differentiated from cTregs and underwent rapid proliferation that was balanced by a high rate of apoptotic cell death. Although eTregs expressed lower levels of Cd25 (IL2RA), they responded well to Il2. cTregs gained access to paracrine Il2 through their expression of Ccr7 (600242), whereas eTregs populating nonlymphoid tissues expressed low Ccr7, did not access Il2-prevalent regions in vivo, and were insensitive to Il2 blockade. eTregs were maintained by signaling through Icos (604558). Smigiel et al. (2014) concluded that there is a fundamental homeostatic subdivision in Treg populations based on their localization and signaling mechanisms in different environments.
Using multiplex, quantitative imaging, Liu et al. (2015) showed that mouse secondary lymphoid tissues contained discrete clusters of highly suppressive Treg cells expressing phosphorylated Stat5 (see 601511). Within the clusters were rare Il2-positive cells that were activated by self-antigens. The local Il2 induction of Stat5 phosphorylation in Treg cells was part of a feedback circuit that limited further autoimmune responses. Tamoxifen-induced loss of T-cell receptor expression in Treg cells reduced their regulatory capacity and disrupted their localization in clusters, resulting in uncontrolled effector T-cell responses. Liu et al. (2015) concluded that autoreactive T cells are regularly activated to cytokine production and physically cluster with T-cell receptor-stimulated Treg cells responding in a negative-feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.
In a mouse model, Zhou et al. (2019) showed that IL2 is acutely required to maintain Treg cells and immunologic homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL2 in T cells did not reduce Treg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group 3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL2, which is induced selectively by IL1-beta (147720). Macrophages in the small intestine produce IL1-beta, and activation of this pathway involves MYD88 (602170)- and NOD2 (605956)-dependent sensing of the microbiota. Loss-of-function studies showed that ILC3-derived IL2 is essential for maintaining Treg cells, immunologic homeostasis, and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL2 by ILC3s was significantly reduced in the small intestine of patients with Crohn disease (see 266600), and this correlated with lower frequencies of Treg cells. Zhou et al. (2019) concluded that their results revealed a previously unappreciated pathway in which a microbiota- and IL1-beta-dependent axis promotes the production of IL2 by ILC3s to orchestrate immune regulation in the intestine.
Crystal Structure
Rickert et al. (2005) presented the 2.8-angstrom crystal structure of a complex between human IL2 and IL2RA, which interact in a docking mode distinct from that of other cytokine receptor complexes. IL2RA is composed of strand-swapped 'sushi-like' domains, unlike the classical cytokine receptor fold. As a result of this domain swap, IL2RA uses a composite surface to dock into a groove on IL2 that also serves as a binding site for antagonist drugs.
Wang et al. (2005) reported the crystal structure of the quaternary complex of IL2 with IL2RA, IL2RB (146710), and IL2RG (308380) at a resolution of 2.3 angstroms. They noted that the antitumor efficacy of recombinant IL2 is mediated by the receptor complex containing IL2RA, IL2RB, and IL2RG on T cells, whereas the toxic side effects reported in clinical trials of recombinant IL2 are mediated by a receptor complex containing only IL2RB and IL2RG on NK cells. Wang et al. (2005) suggested that the structure of the quaternary complex may be used to design IL2 variants specific to the IL2RA/IL2RB/IL2RG complex and not the IL2RB/IL2RG complex to dissociate efficacy and toxicity of recombinant IL2.
Since interleukin-2 and interleukin-2 receptor act as required for the proliferation of T cells, defects in either the ligand or the receptor would be expected to cause severe combined immunodeficiency. Weinberg and Parkman (1990) described a male Salvadoran infant with severe combined immunodeficiency and a specific absence of IL2 mRNA. The IL2 gene was present, indicating that the defect was not due to a sizable deletion. The infant died following bone marrow transplantation. The use of recombinant interleukin-2 in the treatment of such patients was discussed.
Dijkstra et al. (2014) identified an intact third IL2/IL15 family member, Il15l, in reptiles and some mammals, including the agricultural mammals horse, cow, sheep, and pig. In mice and human, the ORF of IL15L is incapacitated. Il15l proteins share only about 21% amino acid identity with IL15, but key residues for interaction with IL15RA are retained. Dijkstra et al. (2014) concluded that the species lineage leading to mammals began with the 3 similar cytokines IL2, IL15, and IL15L. Later in evolution, IL2 and IL2RA acquired a new and specific binding mode, and IL15L was lost in some, but not all, groups of mammals.
Insulin-dependent diabetes-3 (Idd3), on mouse chromosome 3, has a major effect on the development of type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse model of T1D, promoting the infiltration of autoreactive lymphocytes into the pancreas. The Idd3 region also determines the susceptibility to experimental autoimmune encephalomyelitis and autoimmune ovarian dysgenesis induced by neonatal thymectomy, a disease that is dependent on regulatory T cell function. Using a positional cloning strategy, Lyons et al. (2000) showed that Idd3 spans 780 kb and includes the Il2 gene, which encodes a molecule critical for the maintenance of immune homeostasis. Although it had been hypothesized that Il2 is Idd3, the gene encoding Il21 is also a candidate for Idd3 (King et al., 2004).
Yamanouchi et al. (2007) showed that alleles for susceptibility and resistance to autoimmune disease on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL2). In order to test directly that an approximately 2-fold reduction in Il2 underpins the Idd3-linked destabilization of immune homeostasis, they showed that engineered haplodeficiency of Il2 gene expression not only reduced T cell IL2 production by 2-fold, but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2. Reduced Il2 production achieved by either genetic mechanism correlated with reduced function of CD4+ CD25+ regulatory T cells, which are critical for maintaining immune homeostasis.
By RNA sequencing of unstimulated Cd4-positive T cells from Il2-null mice and wildtype mice, Vogelzang et al. (2014) found that Il21, which is adjacent to IL2 on mouse chromosome 3 and human chromosome 4, was highly expressed in the mutant mice compared with wildtype. Mice lacking both Il2 and Il21r (605383), and thus Il21 signaling, had a deficiency of Foxp3-positive regulatory T cells and splenomegaly, similar to Il2-null mice. However, Il2/Il21r double-knockout mice had significantly reduced morbidity and enhanced survival, accompanied by reduced colonic inflammation, fewer B cells, and reduced class-switched antibody compared with Il2-null mice. The absence of Il21 signaling also resulted in reduced hemolytic anemia compared with Il2-null mice. Expansion of T-follicular helper cells and Th17 cells and increased Il22 (605330) were also found in the double-knockout mice. Vogelzang et al. (2014) concluded that IL21 is an important target of immune regulation and proposed that its modulation may ameliorate chronic inflammatory disorders.
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