Genomes and Genes
Gene Symbol: Il21
Description: interleukin 21
Alias: IL-21, interleukin-21
- Zotos D, Coquet J, Zhang Y, Light A, D Costa K, Kallies A, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010;207:365-78 pubmed publisher..The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly...
- Huber M, Brüstle A, Reinhard K, Guralnik A, Walter G, Mahiny A, et al. IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci U S A. 2008;105:20846-51 pubmed publisher..These data highlight IRF4 as a decisive factor during the IL-21-mediated steps of Th17 development by influencing the balance of Foxp3, RORalpha, and RORgammat. ..
- Ma H, Whitters M, Konz R, Senices M, Young D, Grusby M, et al. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma. J Immunol. 2003;171:608-15 pubmed..We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer. ..
- Pelletier M, Bouchard A, Girard D. In vivo and in vitro roles of IL-21 in inflammation. J Immunol. 2004;173:7521-30 pubmed..We conclude that IL-21 is a proinflammatory cytokine, but not a neutrophil agonist. We propose that IL-21 attracts neutrophils indirectly in vivo via a mechanism independent of IL-6, CCL3, CCL5, and CXCL2 production. ..
- McGuire H, Walters S, Vogelzang A, Lee C, Webster K, Sprent J, et al. Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models. Diabetes. 2011;60:867-75 pubmed publisher..These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes. ..
- Spolski R, Kim H, Zhu W, Levy D, Leonard W. IL-21 mediates suppressive effects via its induction of IL-10. J Immunol. 2009;182:2859-67 pubmed publisher..Overall, our data indicate that IL-21 regulates immune responses at least in part by inducing IL-10 and reveal unanticipated immunosuppressive actions for this cytokine. ..
- McGuire H, Vogelzang A, Hill N, Flodstrom Tullberg M, Sprent J, King C. Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus. Proc Natl Acad Sci U S A. 2009;106:19438-43 pubmed publisher..In the first group, which includes the C57BL/6 strain, both Il2 and Il21 were expressed at low levels...
- Ostiguy V, Allard E, Marquis M, Leignadier J, Labrecque N. IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade. J Leukoc Biol. 2007;82:645-56 pubmed..Our data provide a new role for IL-21 in the immune system, which might be used to improve T cell homeostasis in immunocompromised patients. ..
- Hiramatsu Y, Suto A, Kashiwakuma D, Kanari H, Kagami S, Ikeda K, et al. c-Maf activates the promoter and enhancer of the IL-21 gene, and TGF-beta inhibits c-Maf-induced IL-21 production in CD4+ T cells. J Leukoc Biol. 2010;87:703-12 pubmed publisher..Taken together, these results suggest that c-Maf induces IL-21 production directly in CD4(+) T cells by activating IL-21P and the CNS-2 enhancer and that TGF-beta suppresses c-Maf-induced IL-21 production in CD4(+) T cells. ..
- Dienz O, Eaton S, Bond J, Neveu W, Moquin D, Noubade R, et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J Exp Med. 2009;206:69-78 pubmed publisher..Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity. ..
- Barker B, Gladstone M, Gillard G, Panas M, Letvin N. Critical role for IL-21 in both primary and memory anti-viral CD8+ T-cell responses. Eur J Immunol. 2010;40:3085-96 pubmed publisher..These findings indicate that IL-21 is an important mediator of CD4(+) T-cell help to CD8(+) T cells. ..
- Wurster A, Rodgers V, Satoskar A, Whitters M, Young D, Collins M, et al. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J Exp Med. 2002;196:969-77 pubmed..These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-gamma-producing Th1 cells which could serve to amplify a Th2 response. ..
- Brandt K, Singh P, Bulfone Paus S, Rückert R. Interleukin-21: a new modulator of immunity, infection, and cancer. Cytokine Growth Factor Rev. 2007;18:223-32 pubmed..This review intends to give the reader an overview of the recent findings concerning the biology of IL-21 and its physiological role in immunity, infection, and cancer. ..
- Lüthje K, Kallies A, Shimohakamada Y, Belz G, Light A, Tarlinton D, et al. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat Immunol. 2012;13:491-8 pubmed publisher..cells), whose hallmark is expression of the transcriptional repressor Bcl-6, the chemokine receptor CXCR5 and interleukin 21 (IL-21)...
- Fina D, Sarra M, Fantini M, Rizzo A, Caruso R, Caprioli F, et al. Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology. 2008;134:1038-48 pubmed publisher..Neutralization of IL-21 reduced IL-17 secretion by IBD lamina propria lymphocytes. These results indicate that IL-21 is a critical regulator of inflammation and Th17 cell responses in the gut. ..
- Fantini M, Rizzo A, Fina D, Caruso R, Becker C, Neurath M, et al. IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells. Eur J Immunol. 2007;37:3155-63 pubmed..Therefore, IL-21 emerges as a key modulator of TGF-beta signaling, leading to the reciprocal differentiation of T(reg) and Th17 cells. ..
- Di Carlo E, Comes A, Orengo A, Rosso O, Meazza R, Musiani P, et al. IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice. J Immunol. 2004;172:1540-7 pubmed..These data suggest that IL-21 represents a suitable adjuvant in inducing specific CTL responses. ..
- Nurieva R, Yang X, Martinez G, Zhang Y, Panopoulos A, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007;448:480-3 pubmed..IL-21 is therefore an autocrine cytokine that is sufficient and necessary for T(H)17 differentiation, and serves as a target for treating inflammatory diseases. ..
- Harada M, Magara Koyanagi K, Watarai H, Nagata Y, Ishii Y, Kojo S, et al. IL-21-induced Bepsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses. J Exp Med. 2006;203:2929-37 pubmed..BCG-activated PBMCs significantly reduce IgE production by human B cells. These findings provide new insight into the therapeutic effect of BCG in allergic diseases...
- Mehta D, Wurster A, Weinmann A, Grusby M. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc Natl Acad Sci U S A. 2005;102:2016-21 pubmed..These data suggest that there are multiple mechanisms by which Th-cell-subset-specific cytokine genes are regulated. ..
- Petrelli A, Carvello M, Vergani A, Lee K, Tezza S, Du M, et al. IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response. Diabetes. 2011;60:3223-34 pubmed publisher..Blockade of the IL-21/IL-21R pathway could be a precondition for tolerogenic protocols in transplantation. ..
- Parrish Novak J, Dillon S, Nelson A, Hammond A, Sprecher C, Gross J, et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000;408:57-63 pubmed..This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R...
- Kasaian M, Whitters M, Carter L, Lowe L, Jussif J, Deng B, et al. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity. 2002;16:559-69 pubmed..These observations suggest that IL-21 promotes the transition between innate and adaptive immunity. ..
- Wei L, Laurence A, Elias K, O Shea J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem. 2007;282:34605-10 pubmed..Additionally, Stat3 can directly bind the Il21 promoter. IL-21 also induces IL-17 production and expression of the transcription factor, RORgammat...
- Sonderegger I, Kisielow J, Meier R, King C, Kopf M. IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo. Eur J Immunol. 2008;38:1833-8 pubmed publisher..their recruitment to inflamed organs, and the development of autoimmune disease was not affected in il21R(-/-) and il21(-/-) mice in models of myelin oligodendrocyte glycoprotein-induced autoimmune encephalitis and autoimmune ..
- Yi J, Du M, Zajac A. A vital role for interleukin-21 in the control of a chronic viral infection. Science. 2009;324:1572-6 pubmed publisher..Thus, IL-21 serves as a critical helper factor that shapes the functional quality of antiviral CD8+ T cells and is required for viral control. ..
- Freitas do RosÃ¡rio A, Lamb T, Spence P, Stephens R, Lang A, Roers A, et al. IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J Immunol. 2012;188:1178-90 pubmed publisher..Finally, in this model of malaria, we demonstrate that the generation of protective IL10(+)IFN-Î³(+) Th1 cells is dependent on IL-27 signaling and independent of IL-21. ..
- Pesce J, Kaviratne M, Ramalingam T, Thompson R, Urban J, Cheever A, et al. The IL-21 receptor augments Th2 effector function and alternative macrophage activation. J Clin Invest. 2006;116:2044-55 pubmed..Collectively, these results illustrate an essential function for the IL-21R in the development of pathogen-induced Th2 responses, which may have relevance in therapies for both inflammatory and chronic fibrotic diseases. ..
- Ozaki K, Spolski R, Ettinger R, Kim H, Wang G, Qi C, et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol. 2004;173:5361-71 pubmed..Finally, BXSB-Yaa mice, which develop a systemic lupus erythematosus-like disease, have greatly elevated IL-21, suggesting a role for IL-21 in the development of autoimmune disease. ..
- Datta S, SARVETNICK N. IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PLoS ONE. 2008;3:e3118 pubmed publisher..Taken together, our results suggest that IL-21 plays a global role in regulating T cell homeostasis, promoting the continuous adaptation of the T cell lymphoid space. ..
- Bauquet A, Jin H, Paterson A, Mitsdoerffer M, Ho I, Sharpe A, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol. 2009;10:167-75 pubmed publisher..Genetic loss of c-Maf resulted in a defect in IL-21 production and fewer T(H)-17 and T(FH) cells. Thus our data suggest that ICOS-induced c-Maf regulates IL-21 production that in turn regulates the expansion of T(H)-17 and T(FH) cells. ..
- Pene J, Gauchat J, Lécart S, Drouet E, Guglielmi P, Boulay V, et al. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J Immunol. 2004;172:5154-7 pubmed..These results show that IL-21, in addition to promoting growth and differentiation of committed B cells, is a specific switch factor for the production of IgG(1) and IgG(3). ..
- Brandt K, Bulfone Paus S, Foster D, Rückert R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood. 2003;102:4090-8 pubmedb>Interleukin 21 (IL-21) is a newly described cytokine with homology to IL-4 and IL-15. They belong to a cytokine family that uses the common gamma chain for signaling but also have their private high-affinity receptors...
- Moroz A, Eppolito C, Li Q, Tao J, Clegg C, Shrikant P. IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol. 2004;173:900-9 pubmed..These findings indicate that the mechanisms used by IL-21 to promote CD8(+) T cell responses offer unique opportunities for its use in malignant diseases and infections. ..
- Coquet J, Chakravarti S, Smyth M, Godfrey D. Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis. J Immunol. 2008;180:7097-101 pubmed..Thus, our results challenge the notion that IL-21 is a key factor in driving Th17 immunity and disease. ..
- Nurieva R, Chung Y, Hwang D, Yang X, Kang H, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138-49 pubmed publisher..This study thus demonstrates that Tfh is a distinct Th cell lineage. ..
- Bucher C, Koch L, Vogtenhuber C, Goren E, Munger M, Panoskaltsis Mortari A, et al. IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood. 2009;114:5375-84 pubmed publisher..Together, these data indicate that IL-21 suppresses inducible Treg conversion and further suggest that IL-21 blockade is an attractive strategy to reduce GVHD-induced injury. ..
- King I, Mohrs K, Mohrs M. A nonredundant role for IL-21 receptor signaling in plasma cell differentiation and protective type 2 immunity against gastrointestinal helminth infection. J Immunol. 2010;185:6138-45 pubmed publisher..Our studies demonstrate a selective role for IL-21 in plasma cell differentiation in the context of protective antiparasitic type 2 immunity...
- McGuire H, Vogelzang A, Ma C, Hughes W, Silveira P, Tangye S, et al. A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity. Immunity. 2011;34:602-15 pubmed publisherThis study describes a CD4+ T helper (Th) cell subset marked by coexpression of the cytokine interleukin 21 (IL-21) and the gut-homing chemokine receptor CCR9...
- Jang E, Cho S, Park H, Paik D, Kim J, Youn J. A positive feedback loop of IL-21 signaling provoked by homeostatic CD4+CD25- T cell expansion is essential for the development of arthritis in autoimmune K/BxN mice. J Immunol. 2009;182:4649-56 pubmed publisher..Our findings suggest that effective targeting of IL-21-mediated processes may be useful in treating autoimmune arthritis. ..
- Pot C, Jin H, Awasthi A, Liu S, Lai C, Madan R, et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol. 2009;183:797-801 pubmed publisher..ICOS further promotes IL-27-driven Tr1 cells. Each of those elements is essential, because loss of c-Maf, IL-21-signaling, or ICOS decreases the frequency of IL-27-induced differentiation of IL-10-producing Tr1 cells. ..
- Suto A, Wurster A, Reiner S, Grusby M. IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomesodermin expression. J Immunol. 2006;177:3721-7 pubmed..Taken together, these results demonstrate that Eomes plays a role in regulating IFN-gamma production in CD4+ T cells and IL-21 inhibits IFN-gamma production in developing Th1 cells through the repression of Eomes expression. ..
- Eto D, LAO C, DiToro D, Barnett B, Escobar T, Kageyama R, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS ONE. 2011;6:e17739 pubmed publisher..Cumulatively, our data indicates that optimal Tfh formation requires IL-21 and IL-6, and that cytokines alone are insufficient to drive Tfh differentiation. ..
- Brady J, Hayakawa Y, Smyth M, Nutt S. IL-21 induces the functional maturation of murine NK cells. J Immunol. 2004;172:2048-58 pubmed..These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance. ..
- Batten M, Ramamoorthi N, Kljavin N, Ma C, Cox J, Dengler H, et al. IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells. J Exp Med. 2010;207:2895-906 pubmed publisher..Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses. ..
- Herber D, Brown T, Liang S, Young D, Collins M, Dunussi Joannopoulos K. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. J Immunol. 2007;178:3822-30 pubmed..From a clinical standpoint, these results suggest that blocking IL-21 in systemic lupus erythematosus patients may represent a promising novel therapeutic approach. ..
- Wang L, Yu C, Kim H, Liao W, Telford W, Egwuagu C, et al. Key role for IL-21 in experimental autoimmune uveitis. Proc Natl Acad Sci U S A. 2011;108:9542-7 pubmed publisher..Here, we generated Il21-mCherry/Il2-emGFP dual-reporter transgenic mice and showed that development of experimental autoimmune uveitis (EAU)..
- Kwon H, Thierry Mieg D, Thierry Mieg J, Kim H, Oh J, Tunyaplin C, et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity. 2009;31:941-52 pubmed publisher..These results reveal broad cooperative gene regulation by STAT3 and IRF4. ..
- Chen Q, Yang W, Gupta S, Biswas P, Smith P, Bhagat G, et al. IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity. 2008;29:899-911 pubmed publisher..Thus, IBP appears to be important in preventing T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens. ..
- Bessa J, Kopf M, Bachmann M. Cutting edge: IL-21 and TLR signaling regulate germinal center responses in a B cell-intrinsic manner. J Immunol. 2010;184:4615-9 pubmed publisher..Hence, IL-21 acts directly on B cells and cooperates with TLR signaling for optimal B cell responses. ..
- Poholek A, Hansen K, Hernandez S, Eto D, Chandele A, Weinstein J, et al. In vivo regulation of Bcl6 and T follicular helper cell development. J Immunol. 2010;185:313-26 pubmed publisher..These data increase our understanding of Bcl6 regulation in T(FH) cells and their differentiation in vivo and identifies a new surface marker that may be functionally relevant in this subset...
- Kashiwakuma D, Suto A, Hiramatsu Y, Ikeda K, Takatori H, Suzuki K, et al. B and T lymphocyte attenuator suppresses IL-21 production from follicular Th cells and subsequent humoral immune responses. J Immunol. 2010;185:2730-6 pubmed publisher..These results suggest that BTLA signaling suppresses IL-21 production from Tfh cells and subsequent Tfh cell-mediated IgG responses. ..
- Linterman M, Beaton L, Yu D, Ramiscal R, Srivastava M, Hogan J, et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med. 2010;207:353-63 pubmed publisher..In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21...
- Stumhofer J, Silver J, Hunter C. IL-21 is required for optimal antibody production and T cell responses during chronic Toxoplasma gondii infection. PLoS ONE. 2013;8:e62889 pubmed publisher..Therefore, Il21 (-/-) mice were challenged with T...
- Attridge K, Wang C, Wardzinski L, Kenefeck R, Chamberlain J, Manzotti C, et al. IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis. Blood. 2012;119:4656-64 pubmed publisher..The data also suggest a new paradigm whereby cytokines can promote immunity by inhibiting IL-2. ..
- Suto A, Nakajima H, Hirose K, Suzuki K, Kagami S, Seto Y, et al. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C(epsilon) transcription of IL-4-stimulated B cells. Blood. 2002;100:4565-73 pubmedb>Interleukin 21 (IL-21) has recently been identified as a multifunctional cytokine that induces the proliferation of T cells and B cells and differentiation of natural killer cells...
- Novy P, Huang X, Leonard W, Yang Y. Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection. J Immunol. 2011;186:2729-38 pubmed publisher..These results identify a critical role for intrinsic IL-21 signaling in CD8 T cell responses to an acute viral infection in vivo and may help design effective vaccine strategies. ..
- Ozaki K, Spolski R, Feng C, Qi C, Cheng J, Sher A, et al. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298:1630-4 pubmed..This suggests that these gammac-dependent cytokines may be those whose inactivation is primarily responsible for the B cell defect in humans with XSCID. ..
- Chen G, Hardy K, Bunting K, Daley S, Ma L, Shannon M. Regulation of the IL-21 gene by the NF-?B transcription factor c-Rel. J Immunol. 2010;185:2350-9 pubmed publisher..A c-Rel binding site identified in the proximal promoter of il21 is confirmed to bind c-Rel in vitro and in vivo and to regulate expression from the il21 promoter in T cells...
- Rasheed M, Latner D, Aubert R, Gourley T, Spolski R, Davis C, et al. Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J Virol. 2013;87:7737-46 pubmed publisher..Taken together, our results highlight the importance of IL-21 in humoral immunity to viruses...
- Linterman M, Rigby R, Wong R, Yu D, Brink R, Cannons J, et al. Follicular helper T cells are required for systemic autoimmunity. J Exp Med. 2009;206:561-76 pubmed publisher..In contrast, adoptive transfer of sanroque T(FH) cells led to spontaneous GC formation. These findings identify T(FH) dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity. ..
- Publicover J, Goodsell A, Nishimura S, Vilarinho S, Wang Z, Avanesyan L, et al. IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest. 2011;121:1154-62 pubmed publisher..These findings carry implications for therapeutic augmentation of immune responses to HBV and potentially other persistent liver viruses. ..
- Mehta D, Wurster A, Whitters M, Young D, Collins M, Grusby M. IL-21 induces the apoptosis of resting and activated primary B cells. J Immunol. 2003;170:4111-8 pubmed..These studies reveal a novel pathway that mediates B cell apoptosis via the IL-21R and suggest that IL-21 may play a role in regulating B cell homeostasis. ..
- Phares T, DiSano K, Hinton D, Hwang M, Zajac A, Stohlman S, et al. IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol. 2013;263:43-54 pubmed publisher..Viral control was already lost prior to humoral CNS responses, but demyelination remained comparable. These data demonstrate a critical role of IL-21 in regulating CNS immunity, sustaining viral persistence and preventing mortality. ..