HGNC Approved Gene Symbol: IL21
SNOMEDCT: 1173999006;
Cytogenetic location: 4q27 Genomic coordinates (GRCh38): 4:122,610,108-122,621,066 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q27 | ?Immunodeficiency, common variable, 11 | 615767 | Autosomal recessive | 3 |
IL21 is a type I cytokine that shares homology with IL2 (147680), IL4 (147780), and IL15 (600554). IL21 is mainly produced by activated T cells, but it targets a broad range of lymphoid and myeloid cells and therefore regulates innate and acquired immune responses (review by Brandt et al., 2007).
Parrish-Novak et al. (2000) identified a novel type I cytokine receptor, IL21R (605383). By analysis of cDNA libraries derived from activated T cells expressing a protein that induces growth in cells expressing IL21R, they isolated a cDNA encoding IL21. The predicted 162-amino acid protein, which is 57% identical to the mouse sequence, contains a 31-amino acid signal peptide; a 4-helix-bundle cytokine domain homologous to IL2, IL4, and IL15; and 2 pairs of cys residues in the same positions as those in IL15. RT-PCR, but not Northern blot analysis, detected IL21 in activated CD4 (186940)-positive T cells, but not in CD8 (see 186910)-positive T cells, B cells, or monocytes.
By radiation hybrid analysis, Parrish-Novak et al. (2000) mapped the IL21 gene to chromosome 4q26-q27, near the IL2 gene.
Mehta et al. (2005) noted that, unlike other mouse Th2 cytokine genes, which are clustered on chromosome 11, the Il21 gene maps to chromosome 3.
Parrish-Novak et al. (2000) showed that IL21 stimulates B-cell proliferation in an anti-CD40 (109535)-dependent manner but inhibits proliferation stimulated by IL4 plus anti-IgM. IL21 augments anti-CD3 (see 186740)-mediated stimulation of the proliferation of naive (CD45RA-positive) but not memory (CD45RO-positive) T cells. In the presence of IL15, IL21 stimulates the proliferation of bone marrow progenitor cells and the expression of the NK-cell marker CD56. Functional analysis of CD34-positive hematopoietic progenitor cells (see 142230) determined that the combination of IL15, IL21, and FLT3LG (600007) stimulates an increase in total cell numbers and the proportion of cells that are positive for CD56 and CD16 (146740). Enhancement of NK-cell function by IL21 was not as great as that observed with IL2 or IL15.
Mehta et al. (2003) noted that the biologic effects of IL21 on NK cells differ between species, with human IL21 enhancing NK cell proliferation and murine Il21 inhibiting NK cell proliferation. They analyzed the effects of Il21 on murine B cells and extended this functional divergence to the lymphoid compartment. In contrast to human IL21, murine Il21 failed to enhance proliferation of B cells costimulated with anti-CD40. In addition, murine Il21 induced apoptosis of primary and resting B cells via Bcl2 (151430) and Bclxl (600039) mechanisms.
By promoter analysis and genetic experiments with Tbet (TBX21; 604895)- and Nfatc2 (600490)-deficient mice, Mehta et al. (2005) demonstrated that Il21 is regulated by Th cell subset-specific action of Tbet and Nfatc2. They showed that Nfatc2 promotes expression of Il21 in Th2 cells, whereas Tbet represses its expression by inhibiting binding of Nfatc2 to the Il21 promoter in Th1 cells.
Ettinger et al. (2005) found that IL21 stimulation of either CD27 (TNFRSF7; 186711)-positive memory B cells or naive cord blood B cells following engagement of CD40 induced extensive proliferation, class switch recombination, and plasma cell differentiation without inducing somatic hypermutation. The effects of IL21 were more pronounced after engagement of both B-cell receptor (BCR) and CD40, but were minimal following engagement of BCR alone. IL2 enhanced the effects of IL21, whereas IL4 prevented them. IL21 costimulation potently induced expression of BLIMP1 (PRDM1; 603423), AICDA (605257), and IgG in B cells. Ettinger et al. (2005) concluded that IL21 plays a central role in class switch recombination and plasma cell differentiation during T cell-dependent B-cell responses.
Using ELISA, Pene et al. (2006) found that recombinant human IL21 enhanced proliferation and IgE (see 147180) production by both CD19 (107265)-positive/CD27-negative naive and CD19-positive/CD 27-positive memory B lymphocytes after stimulation with anti-CD40 and recombinant IL4. However, reporter assays and Northern blot analysis showed that recombinant IL21 did not affect IgE constant region promoter activation or mRNA expression in response to anti-CD40 and recombinant IL4. In the absence of anti-CD40, recombinant IL21 induced IFNG (147570) production and inhibition of recombinant IL4-induced IgE production. Individuals heterozygous for the -83T-C promoter polymorphism in the IL21R gene (605383.0001) had reduced recombinant IL21-induced IFNG production and inhibition of IgE synthesis compared with individuals with wildtype IL21R. Pene et al. (2006) concluded that IL21 differentially regulates IgE production, in part, due to a polymorphism in the IL21R gene.
Nurieva et al. (2007) showed that IL21 is a cytokine highly expressed by mouse T(H)17 cells. Il21 is induced by IL6 (147620) in activated T cells, a process that is dependent on STAT3 (102582) but not on ROR-gamma (see RORC, 602943). IL21 potently induces T(H)17 differentiation and suppresses FOXP3 (300292) expression, which requires STAT3 and ROR-gamma. Nurieva et al. (2007) concluded that IL21 deficiency impairs the generation of T(H)17 cells and results in protection against experimental autoimmune encephalomyelitis. IL21 is therefore an autocrine cytokine that is sufficient and necessary for T(H)17 differentiation, and serves as a target for treating inflammatory diseases.
By mutation analysis, Zeng et al. (2007) showed that tyr510 of mouse Il21r was required for Il21-induced phosphorylation of Stat1 (600555) and Stat3 and for maximal Il21-mediated proliferation of Il3 (147740)-dependent pro-B Ba/F3 cells. Cd8-positive T cells from Stat1/Stat3 double-knockout mice exhibited decreased proliferation in response to Il21 plus Il15. Il21 weakly induced phosphorylation of Shc (SHC1; 600560) and Akt (AKT1; 164730), and consistent with this, specific inhibitors of the MAPK (see 176948) and PI3K (see 601232) pathways inhibited Il21-mediated proliferation. Zeng et al. (2007) concluded that the JAK (see 147795)-STAT, MAPK, and PI3K pathways are involved in IL21 signaling.
Brandt et al. (2007) reviewed IL21 function and the roles of IL21 in immunity, infection, and cancer.
Yang et al. (2008) confirmed that whereas IL1-beta (147720) and IL6 (147620) induce IL17A (603149) secretion from human central memory CD4+ T cells, TGF-beta (190180) and IL21 uniquely promote the differentiation of human naive CD4+ T cells into TH17 cells accompanied by expression of the transcription factor RORC2 (see 602943).
Jin et al. (2009) found increased expression of IL21 and IL21R in skin lesions of patients with atopic dermatitis (see 603165) compared to controls. IL21 was expressed by mononuclear leukocytes that infiltrated the dermis and was weakly detected in the epidermis of skin lesions, particularly in areas with more severe acute eczematous changes. IL21R expression was observed in epidermal keratinocytes of skin lesions and along the dermal/epidermal junction in a granular expression pattern. In contrast, normal skin had no IL21 protein expression and only weak IL21R expression.
Caruso et al. (2009) observed high IL21 protein and mRNA levels in skin lesions from patients with psoriasis (see 177900) compared to skin samples from nonlesional skin and from controls. IL21 was mostly produced by CD4+ T cells. IL21 transcript levels and IL21-expressing circulating T cells were also found in peripheral blood of individuals with psoriasis. Lesional skin, T cells, B cells, and natural killer cells expressed the IL21 receptor. Treatment of keratinocytes from nonlesional skin caused epidermal hyperplasia and infiltration of the epidermis and dermis with inflammatory cells. In a human psoriasis xenograft mouse model, IL21 converted uninvolved skin into psoriatic plaques, and blockade of IL21 resolved inflammation and reduced keratinocyte proliferation. The findings indicated a role for IL21 in the epidermal hyperplasia of psoriasis.
B10 cells are human and mouse regulatory B cells with the ability to express the inhibitory cytokine IL10 (124092). Yoshizaki et al. (2012) used a mouse model for multiple sclerosis to demonstrate that B10 cell maturation into functional IL10-secreting effector cells that inhibit in vivo autoimmune disease requires IL21 and CD40 (109535)-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. Yoshizaki et al. (2012) suggested that the ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to therapies.
Berglund et al. (2013) noted that a feature of autosomal dominant hyper-IgE syndrome (147060) due to STAT3 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. 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. They proposed that lack of this secondary effect of IL21 may amplify humoral immunodeficiency in patients with mutations in STAT3, IL2RG (308380), or IL21R due to impaired IL21 responsiveness.
For discussion of a possible association between variation in the IL21 gene and susceptibility to psoriasis or autoimmune disorders, see PSORS3 (601454) and CELIAC6 (611598), respectively.
In a boy, born of consanguineous Turkish parents, with common variable immunodeficiency-11 (CVID11; 615767) presenting as inflammatory bowel disease, Salzer et al. (2014) identified a homozygous missense mutation in the IL21 gene (L49P; 605384.0001). The mutation was found using a combination of homozygosity mapping and exome sequencing. Functional studies showed that the mutation caused a loss of IL21-induced signaling and impaired B-cell differentiation.
Kasaian et al. (2002) generated Il21r-deficient mice by homologous recombination and deletion of exon 1. The mice had normal NK cell development and responses to poly I:C in vivo or IL15 in vitro, but not to IL21. In wildtype mice, IL21 limited the growth but not activation of NK cells, but not T cells, in response to IL15 or IL2 in antigen-free cultures. IL21 could boost the function of activated NK cells from these mice without promoting NK cell viability or preventing apoptosis. CD8-positive T cells from either wildtype or Il21r -/- mice treated with IL15 proliferated and expressed high levels of CD44 (107269), a marker for 'memory' T cells. Addition of IL21 counteracted the effects of IL15 in wildtype but not Il21r-deficient mice and also prevented the expansion of cells expressing the IFNG receptor, CD119 (IFNGR1; 107470), as well as those expressing IL2RA and IL2RB/IL15RB (CD122; 146710), but not IL2RG. IL21 enhanced proliferation and effector functions of wildtype cytolytic T cells stimulated with either anti-CD3 or allogeneic cells. Kasaian et al. (2002) proposed that IL21 promotes the transition between innate and adaptive immunity.
Korn et al. (2007) showed that Il6 (147620)-deficient mice do not develop a T(H)17 response, and their peripheral repertoire is dominated by Foxp3+ T regulatory cells. However, deletion of T regulatory cells led to the reappearance of T(H)17 cells in Il6-null mice, suggesting an additional pathway by which T(H)17 might be generated in vivo. Korn et al. (2007) showed that an IL2 cytokine family member, IL21, cooperates with TGF-beta (190180) to induce T(H)17 cells in naive Il6-null T cells and that IL21-receptor-deficient T cells are defective in generating a T(H)17 response.
Using different strains of lymphocytic choriomeningitis virus (LCMV) to induce acute or chronic infection in mice, Elsaesser et al. (2009) found that high levels of Il21 were produced by Cd4-positive T cells in the chronic phase of infection, at which time Il2 production was extinguished. Mice lacking Il21r exhibited an increased presence of virus-specific Cd4-positive T cells but an exhaustion of Cd8-positive T cells, with little or no effect on antigen-presenting cells or B cells, during chronic LCMV infection. Elsaesser et al. (2009) concluded that IL21 sustains CD8-positive T-cell effector activity and provides a mechanism of CD4-positive T-cell help during chronic viral infection.
Using acute and chronic LCMV strains, Yi et al. (2009) found that wildtype and Il21 -/- mice controlled acute infection, but that Il21 -/- mice had reduced Il2-, Ifng-, and Tnf (191160)-producing Cd8-positive T cells. Il21 +/- mice had a phenotype intermediate between Il21 -/- mice and wildtype mice. Administration of Il21 to chronic LCMV-infected Cd4 -/- mice resulted in lower viral titers, but most mice became moribund, suggesting care in the use of IL21 for treatment of chronic viral infections.
Frohlich et al. (2009) showed that Il21r -/- mice had normal Cd8-positive T-cell expansion, effector function, memory homeostasis, and recall response during acute and after resolved infections, but not during chronic infections. They proposed that IL21-IL21R signaling is required during chronic viral infections and may also be important in responses to other persisting antigens, such as tumors.
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, 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.
Brodeur et al. (2015) found that Il21 played a critical role in the fibrotic response associated with the bleomycin mouse model of sterile lung injury. Mice lacking Il21 or Il21r developed inflammation, but not fibrosis, in response to bleomycin treatment. Il21 drove activation and expansion of Il13 (147683)-producing type-2 cytotoxic T cells (Tc2 cells), which served as a critical link between inflammation and fibrosis.
In a boy, born of consanguineous Turkish parents, with common variable immunodeficiency-11 (CVID11; 615767), Salzer et al. (2014) identified a homozygous c.147T-C transition in the IL21 gene, resulting in a leu49-to-pro (L49P) substitution at a highly conserved residue. The mutation, which was found using a combination of homozygosity mapping and exome sequencing, segregated with the disorder and was not present in the dbSNP (build 135) or 1000 Genomes Project databases. In vitro functional expression assays showed that the mutant IL21 protein did not induce STAT3 (102582) phosphorylation and resulted in decreased proliferation of B cells. In contrast, patient cells showed normal response to wildtype IL21. Based on these results and structural modeling, Salzer et al. (2014) proposed that the IL21 mutation interfered with binding to IL21R (605383). The patient presented in infancy with severe diarrhea and inflammatory bowel disease as well as recurrent severe respiratory infections. Two sibs had died in infancy of chronic diarrhea. Salzer et al. (2014) discussed the association between IL21 immunodeficiency and early-onset inflammatory bowel disease.
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