Genomes and Genes
Gene Symbol: Il2
Description: interleukin 2
Alias: Il-2, interleukin-2, T-cell growth factor, TCGF
- Knoechel B, Lohr J, Kahn E, Bluestone J, Abbas A. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med. 2005;202:1375-86 pubmed..Thus, a peripheral T cell reaction to a systemic antigen goes through a phase of effector cell-mediated pathology followed by T reg cell-mediated recovery, and both require the growth factor IL-2. ..
- Jones T, Ha J, Williams M, Adams A, Durham M, Rees P, et al. The role of the IL-2 pathway in costimulation blockade-resistant rejection of allografts. J Immunol. 2002;168:1123-30 pubmed..Interestingly, depletion of CD4+ T cells, but not CD8+ cells, prevents prolongation in allograft survival, suggesting an IL-2-independent role for regulation in extended survival. ..
- Wiesel M, Joller N, Ehlert A, Crouse J, Spörri R, Bachmann M, et al. Th cells act via two synergistic pathways to promote antiviral CD8+ T cell responses. J Immunol. 2010;185:5188-97 pubmed publisher..Second, Th cells provide CD8(+) T cells with IL-2, thereby enhancing their survival. Thus, Th cells are at the center of an important communication loop with a central role for IL-2/IL-2R and bioactive IL-12. ..
- Miller J, Stevens E, Smith D, Wight T, Wrenshall L. Perlecan: a major IL-2-binding proteoglycan in murine spleen. Immunol Cell Biol. 2008;86:192-9 pubmed..Identification of perlecan as a major heparan sulfate proteoglycan that binds IL-2 has implications for both the localization and regulation of IL-2 in vivo. ..
- Wang G, Khattar M, Guo Z, Miyahara Y, Linkes S, Sun Z, et al. IL-2-deprivation and TGF-beta are two non-redundant suppressor mechanisms of CD4+CD25+ regulatory T cell which jointly restrain CD4+CD25- cell activation. Immunol Lett. 2010;132:61-8 pubmed publisher..In conclusion, these two suppressive mechanisms acting in concert may be necessary to effectively restrain the early activation of Tconvs. ..
- Nagahama K, Ogawa A, Shirane K, Shimomura Y, Sugimoto K, Mizoguchi A. Protein kinase C theta plays a fundamental role in different types of chronic colitis. Gastroenterology. 2008;134:459-69 pubmed..PKCtheta serves as a common and fundamental signaling molecule in the development of different types of colitis and may represent an attractive target for treating inflammatory bowel disease. ..
- Cho J, Boyman O, Kim H, Hahm B, Rubinstein M, Ramsey C, et al. An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. J Exp Med. 2007;204:1787-801 pubmed..IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed. ..
- Bayer A, Yu A, Adeegbe D, Malek T. Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period. J Exp Med. 2005;201:769-77 pubmed..However, for normal neonates, blockade of IL-2 decreased T(reg) cells in both the thymus and LN. Therefore, two steps of T(reg) cell development depend upon IL-2 in neonatal mice, thymus production, and subsequent expansion in the LN. ..
- de la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol. 2004;34:2480-8 pubmed..We propose the parakrine uptake of soluble mediators as a flexible mechanism to adapt Treg activity to the strength of the responder T cell reaction. ..
- Vosshenrich C, Ranson T, Samson S, Corcuff E, Colucci F, Rosmaraki E, et al. Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo. J Immunol. 2005;174:1213-21 pubmed..Surprisingly, the few residual NK cells generated in absence of IL-15 appear relatively mature, expressing a variety of Ly49 receptors and demonstrating lytic and cytokine production capacity. ..
- McNally A, Hill G, Sparwasser T, Thomas R, Steptoe R. CD4+CD25+ regulatory T cells control CD8+ T-cell effector differentiation by modulating IL-2 homeostasis. Proc Natl Acad Sci U S A. 2011;108:7529-34 pubmed publisher..Furthermore, a regulatory loop exists between Treg and CD8(+) effector T cells, where IL-2 produced during CD8(+) T-cell effector differentiation promotes Treg expansion. ..
- Williams M, Tyznik A, Bevan M. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006;441:890-3 pubmed..These results have important implications for the development of vaccination or immunotherapeutic strategies aimed at boosting memory T-cell function. ..
- Wrenshall L, Platt J, Stevens E, Wight T, Miller J. Propagation and control of T cell responses by heparan sulfate-bound IL-2. J Immunol. 2003;170:5470-4 pubmed..These findings necessitate a new look at how IL-2 regulates immune responses and support the notion that the microenvironment plays a determining role in modulating the character of immune responses. ..
- Nelson B. Interleukin-2 signaling and the maintenance of self-tolerance. Curr Dir Autoimmun. 2002;5:92-112 pubmed..In this regard, perhaps new insights into this important issue can be gained by better defining when and where IL-2 signaling normally occurs in wild-type animals and the functional status of the T cells involved. ..
- Antov A, Yang L, Vig M, Baltimore D, Van Parijs L. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol. 2003;171:3435-41 pubmed..Furthermore, transient activation of STAT5 is sufficient to increase CD25(+)CD4(+) T reg numbers in IL-2-deficient mice. Our study uncovers an essential role for STAT5 in maintaining CD25(+)CD4(+) T reg homeostasis and self-tolerance. ..
- Chen Y, Haines C, Gutcher I, Hochweller K, Blumenschein W, McClanahan T, et al. Foxp3(+) regulatory T cells promote T helper 17 cell development in vivo through regulation of interleukin-2. Immunity. 2011;34:409-21 pubmed publisher..Rather, regulation of IL-2 availability and resultant signaling through CD25 by Treg cells was found to play an important role. ..
- Dooms H, Wolslegel K, Lin P, Abbas A. Interleukin-2 enhances CD4+ T cell memory by promoting the generation of IL-7R alpha-expressing cells. J Exp Med. 2007;204:547-57 pubmed..These results identify IL-2 as a factor regulating IL-7Ralpha expression and, consequently, memory T cell homeostasis in vivo. ..
- Krutzik P, Clutter M, Nolan G. Coordinate analysis of murine immune cell surface markers and intracellular phosphoproteins by flow cytometry. J Immunol. 2005;175:2357-65 pubmed
- Guo Z, Khattar M, Schroder P, Miyahara Y, Wang G, He X, et al. A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells. J Immunol. 2013;190:3153-62 pubmed publisher..These findings advance the understanding of iTreg differentiation and may facilitate the therapeutic use of iTregs in immune disorders. ..
- Dai Z, Konieczny B, Lakkis F. The dual role of IL-2 in the generation and maintenance of CD8+ memory T cells. J Immunol. 2000;165:3031-6 pubmed..Thus, IL-2-based vaccine strategies or immunosuppressive regimens that target IL-2 should take into account the divergent roles of IL-2 in CD8+ T cell immunity. ..
- Fontenot J, Rasmussen J, Gavin M, Rudensky A. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142-51 pubmed..Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained ..
- Bihl F, Pecheur J, Breart B, Poupon G, Cazareth J, Julia V, et al. Primed antigen-specific CD4+ T cells are required for NK cell activation in vivo upon Leishmania major infection. J Immunol. 2010;185:2174-81 pubmed publisher..Our results reveal an unappreciated role for Ag-specific CD4(+) T cells in the initiation of NK cell activation in vivo upon L. major infection and demonstrate bidirectional regulations between innate and adaptive immunity. ..
- Liao W, Lin J, Wang L, Li P, Leonard W. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat Immunol. 2011;12:551-9 pubmed publisher..T(H)1 differentiation was also impaired in mouse Il2(-/-) T cells but was restored by IL-12RÎ²2 expression...
- Yang X, Ghoreschi K, Steward Tharp S, Rodriguez Canales J, Zhu J, Grainger J, et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol. 2011;12:247-54 pubmed publisherb>Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production...
- Nelson B. IL-2, regulatory T cells, and tolerance. J Immunol. 2004;172:3983-8 pubmedIL-2 is a potent T cell growth factor that for many years was assumed to amplify lymphocyte responses in vivo...
- Qui H, Hagymasi A, Bandyopadhyay S, St Rose M, Ramanarasimhaiah R, Menoret A, et al. CD134 plus CD137 dual costimulation induces Eomesodermin in CD4 T cells to program cytotoxic Th1 differentiation. J Immunol. 2011;187:3555-64 pubmed publisher..This mechanism might be therapeutically useful because CD134 plus CD137 dual costimulation induced CD4 T cell-dependent tumoricidal function in a mouse melanoma model. ..
- Wolf M, Schimpl A, Hunig T. Control of T cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(-) and CD4(+)CD25(+) T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol. 2001;31:1637-45 pubmed..IL-2 deficiency therefore may upset T cell homeostasis by two distinct mechanisms: the failure to program expanding T cells for apoptosis, and the failure to generate functional CD4(+)CD25(+) regulatory cells. ..
- Burchill M, Yang J, Vogtenhuber C, Blazar B, Farrar M. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol. 2007;178:280-90 pubmed..Finally, STAT5 binds to the promoter of the foxp3 gene suggesting that IL-2Rbeta-dependent STAT5 activation promotes Treg differentiation by regulating expression of foxp3. ..
- Almeida A, Zaragoza B, Freitas A. Indexation as a novel mechanism of lymphocyte homeostasis: the number of CD4+CD25+ regulatory T cells is indexed to the number of IL-2-producing cells. J Immunol. 2006;177:192-200 pubmed..The present study highlights that maintenance of proportions between different lymphocyte subsets may also be critical for the immune system and are under strict homeostatic control. ..
- Laurence A, Tato C, Davidson T, Kanno Y, Chen Z, Yao Z, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007;26:371-81 pubmed..We conclude that in addition to the promotion of activation-induced cell death of lymphocytes and the generation of Treg cells, inhibition of Th17 polarization appears to be an important function of IL-2. ..
- Ghiasi H, Osorio Y, Perng G, Nesburn A, Wechsler S. Overexpression of interleukin-2 by a recombinant herpes simplex virus type 1 attenuates pathogenicity and enhances antiviral immunity. J Virol. 2002;76:9069-78 pubmed..These results suggest that IL-2 expression by recombinant HSV-1 reduces virulence and that depletion of IL-2 or T cells increases virulence in HSV-1-infected mice. ..
- Bae J, Park D, Lee Y, Jeoung D. Interleukin-2 promotes angiogenesis by activation of Akt and increase of ROS. J Microbiol Biotechnol. 2008;18:377-82 pubmed..IL-2 increased angiogenesis in an animal model and tube formation in HUVECs. The effect of IL-2 on angiogenesis and tube formation was mediated by ROS and Akt. This is the first report that IL-2 promotes angiogenesis. ..
- Mostbock S, Lutsiak M, Milenic D, Baidoo K, Schlom J, Sabzevari H. IL-2/anti-IL-2 antibody complex enhances vaccine-mediated antigen-specific CD8+ T cell responses and increases the ratio of effector/memory CD8+ T cells to regulatory T cells. J Immunol. 2008;180:5118-29 pubmed..This phenomenon can thus potentially be used in the enhancement of immune responses to vaccination. ..
- Stahl M, Dijkers P, Kops G, Lens S, Coffer P, Burgering B, et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol. 2002;168:5024-31 pubmed..Thus, we propose that inactivation of FoxO transcription factors by IL-2 plays a critical role in T cell proliferation and survival. ..
- Busse D, de la Rosa M, Hobiger K, Thurley K, Flossdorf M, Scheffold A, et al. Competing feedback loops shape IL-2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proc Natl Acad Sci U S A. 2010;107:3058-63 pubmed publisher..The present findings explain how IL-2 can play two distinct roles in immune regulation and point to a hitherto largely unexplored spatiotemporal complexity of cytokine signaling. ..
- Yamashita M, Ukai Tadenuma M, Miyamoto T, Sugaya K, Hosokawa H, Hasegawa A, et al. Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci. J Biol Chem. 2004;279:26983-90 pubmed..Thus, GATA3 plays important roles in the maintenance of the Th2 phenotype and continuous chromatin remodeling of the specific Th2 cytokine gene locus through cell division. ..
- Humrich J, Morbach H, Undeutsch R, Enghard P, Rosenberger S, Weigert O, et al. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proc Natl Acad Sci U S A. 2010;107:204-9 pubmed publisher..The reversibility of this homeostatic Treg disorder provides promising approaches for the treatment of SLE. ..
- Adachi S, Rothenberg E. Cell-type-specific epigenetic marking of the IL2 gene at a distal cis-regulatory region in competent, nontranscribing T-cells. Nucleic Acids Res. 2005;33:3200-10 pubmed..heritably for activation, we have used chromatin immunoprecipitation to map histone modifications across the murine IL2 locus, from -10.2 through +0.25 kb, in induction-competent and incompetent cells...
- Liu Y, Zhang P, Li J, Kulkarni A, Perruche S, Chen W. A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol. 2008;9:632-40 pubmed publisher..recovery of Foxp3+ thymocytes was attributable mainly to overproduction of and heightened responsiveness to interleukin 2, as genetic ablation of interleukin 2 in TbetaRI-mutant mice resulted in a complete absence of CD4+CD25+Foxp3+ ..
- Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201:723-35 pubmed..Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease. ..
- Gong D, Malek T. Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production. J Immunol. 2007;178:242-52 pubmed..Collectively, these findings indicate that there is a negative feedback regulatory loop in activated T cells such that IL-2 inhibits its own production through induction of Blimp-1 while promoting an effector cell phenotype. ..
- Liao W, Schones D, Oh J, Cui Y, Cui K, Roh T, et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol. 2008;9:1288-96 pubmed publisher..expression, T cell receptor-induced IL-4Ralpha expression was normal in Il4(-/-) cells but was much lower in Il2(-/-) cells. Notably, forced IL-4Ralpha expression restored the T(H)2 differentiation of Il2(-/-) cells...
- Wilson E, Livingstone A. Cutting edge: CD4+ T cell-derived IL-2 is essential for help-dependent primary CD8+ T cell responses. J Immunol. 2008;181:7445-8 pubmed..We suggest that it is also a critical component of help for CD8(+) T cell responses to pathogens, because protective memory also requires CD8(+) T cell stimulation by IL-2 during priming. ..
- Chen Q, Kim Y, Laurence A, Punkosdy G, Shevach E. IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol. 2011;186:6329-37 pubmed publisher..Administration of IL-2 in vivo results in stabilization of Foxp3 expression and may prove to be a valuable adjunct for the use of iTreg for the treatment of autoimmune diseases. ..
- Gasteiger G, Hemmers S, Firth M, Le Floc h A, Huse M, Sun J, et al. IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J Exp Med. 2013;210:1167-78 pubmed publisher..Our results suggest that IL-2-dependent adaptive-innate lymphocyte cross talk tunes NK cell reactivity and that T reg cells restrain NK cell cytotoxicity by limiting the availability of IL-2. ..
- Waithman J, Gebhardt T, Davey G, Heath W, Carbone F. Cutting edge: Enhanced IL-2 signaling can convert self-specific T cell response from tolerance to autoimmunity. J Immunol. 2008;180:5789-93 pubmed..Therefore, enhanced IL-2 signaling can act as a major selector between tolerance and autoimmunity. ..
- Pipkin M, Sacks J, Cruz Guilloty F, Lichtenheld M, Bevan M, Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity. 2010;32:79-90 pubmed publisher..Thus, inflammation influences both effector and memory CTL differentiation, whereas persistent IL-2 stimulation promotes effector at the expense of memory CTL development. ..
- Janas M, Groves P, Kienzle N, Kelso A. IL-2 regulates perforin and granzyme gene expression in CD8+ T cells independently of its effects on survival and proliferation. J Immunol. 2005;175:8003-10 pubmed..Together, these findings indicate that IL-2 can directly regulate perforin and granzyme gene expression in CD8+ T cells independently of its effects on cell survival and proliferation. ..
- Dooms H, Kahn E, Knoechel B, Abbas A. IL-2 induces a competitive survival advantage in T lymphocytes. J Immunol. 2004;172:5973-9 pubmed..Therefore, IL-2 enhances competitiveness for survival in CD4(+) T cells, thereby facilitating the development of a memory population. ..
- Martins G, Cimmino L, Liao J, Magnusdottir E, Calame K. Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J Exp Med. 2008;205:1959-65 pubmed publisher..that one critical activity of Blimp-1 in T cells is to repress IL-2, and that it does so by direct repression of Il2 transcription, and also by repression of Fos transcription...
- Waidmann M, Bechtold O, Frick J, Lehr H, Schubert S, Dobrindt U, et al. Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology. 2003;125:162-77 pubmed..In IL-2-/- mice, B. vulgatus mpk protects against E. coli mpk-triggered colitis by an unknown mechanism. E. coli Nissle does not induce colitis. Various bacterial species common to the microflora differ in their ability to trigger IBD. ..
- Kang H, Zhang D, Degauque N, Mariat C, Alexopoulos S, Zheng X. Effects of cyclosporine on transplant tolerance: the role of IL-2. Am J Transplant. 2007;7:1907-16 pubmed..The combination of IL-2/Fc and cyclosporine treatment may provide a new clinical strategy to promote transplant tolerance. ..
- Sitrin J, Ring A, Garcia K, Benoist C, Mathis D. Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. J Exp Med. 2013;210:1153-65 pubmed publisher..Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets. ..
- Létourneau S, van Leeuwen E, Krieg C, Martin C, Pantaleo G, Sprent J, et al. IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25. Proc Natl Acad Sci U S A. 2010;107:2171-6 pubmed publisher..These data suggest an unpredicted role for CD25 in IL-2 homeostasis. ..
- Sharma R, Fu S, Ju S. IL-2: a two-faced master regulator of autoimmunity. J Autoimmun. 2011;36:91-7 pubmed publisher..Whether IL-2 is also required for autoimmune disease development is less clear as Il2(-/)(-) mice themselves spontaneously develop multi-organ inflammation (MOI)...
- Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo M. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007;8:1353-62 pubmed..Thus, cytokine deprivation-induced apoptosis is a prominent mechanism by which T(reg) cells inhibit effector T cell responses. ..
- French A, Sjölin H, Kim S, Koka R, Yang L, Young D, et al. DAP12 signaling directly augments proproliferative cytokine stimulation of NK cells during viral infections. J Immunol. 2006;177:4981-90 pubmed..The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate. ..
- Oestreich K, Mohn S, Weinmann A. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol. 2012;13:405-11 pubmed publisher..Here we found that high concentrations of interleukin 2 (IL-2) inhibited Bcl-6 expression in polarized T(H)1 cells...
- Vang K, Yang J, Mahmud S, Burchill M, Vegoe A, Farrar M. IL-2, -7, and -15, but not thymic stromal lymphopoeitin, redundantly govern CD4+Foxp3+ regulatory T cell development. J Immunol. 2008;181:3285-90 pubmed