Genomes and Genes
Gene Symbol: interleukin 2
Description: interleukin 2
Alias: IL-2, TCGF, lymphokine, interleukin-2, T cell growth factor, aldesleukin, involved in regulation of T-cell clonal expansion
Products: interleukin 2
- Adamovic S, Amundsen S, Lie B, Gudjónsdóttir A, Ascher H, Ek J, et al. Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families. Genes Immun. 2008;9:364-7 pubmed publisher..001 and 0.002, respectively). However, we found no association with the FcgammaRIIa rs1801274 G>A polymorphism (P-value=0.3). In conclusion, our results support the KIAA1109/Tenr/IL2/IL21 region as a true CD susceptibility region. ..
- Lin Y, Wan L, Sheu J, Huang C, Lin C, Lan Y, et al. G/T polymorphism in the interleukin-2 exon 1 region among Han Chinese systemic lupus erythematosus patients in Taiwan. Clin Immunol. 2008;129:36-9 pubmed publisher..01-17.51) and (c) a significantly lower G allele frequency in SLE patients with discoid rash (P=0.019; OR=0.41; 95% CI=0.19-0.88). Our results suggest that this polymorphism may be involved in the genetic background of Taiwanese SLE. ..
- Marquez A, Orozco G, Martinez A, Palomino Morales R, Fernandez Arquero M, Mendoza J, et al. Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease. Am J Gastroenterol. 2009;104:1968-75 pubmed publisher..Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism. ..
- Maiti A, Kim Howard X, Viswanathan P, Guillén L, Rojas Villarraga A, Deshmukh H, et al. Confirmation of an association between rs6822844 at the Il2-Il21 region and multiple autoimmune diseases: evidence of a general susceptibility locus. Arthritis Rheum. 2010;62:323-9 pubmed publisher..Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations. ..
- Christensen U, Haagerup A, Binderup H, Vestbo J, Kruse T, Børglum A. Family based association analysis of the IL2 and IL15 genes in allergic disorders. Eur J Hum Genet. 2006;14:227-35 pubmed..We suggest that the observed overtransmission of the T allele of this SNP may convey increased susceptibility to allergic disease by skewing the Th1/Th2 balance towards Th2. ..
- Hollis Moffatt J, Chen Xu M, Topless R, Dalbeth N, Gow P, Harrison A, et al. Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets: confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance. Arthritis Res Ther. 2010;12:R116 pubmed publisher..The KIAA1109-TENR-IL2-IL21 locus also confers susceptibility to other autoimmune phenotypes with a heterogeneous pattern of association. ..
- Wuest S, Edwan J, Martin J, Han S, Perry J, CARTAGENA C, et al. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med. 2011;17:604-9 pubmed publisher..Our data reveal a previously unknown mechanism for the IL-2 receptor system in DC-mediated activation of T cells. ..
- Shahram F, Nikoopour E, Rezaei N, Saeedfar K, Ziaei N, Davatchi F, et al. Association of interleukin-2, interleukin-4 and transforming growth factor-beta gene polymorphisms with Behcet's disease. Clin Exp Rheumatol. 2011;29:S28-31 pubmed..Cytokine single nucleotide polymorphisms could play a role in the pathophysiology of BD. The results of this study could suggest a tendency towards higher production of IL-2 and lower production of IL-4 in the patients with BD. ..
- Mittal R, Manchanda P. Association of interleukin (IL)-4 intron-3 and IL-6 -174 G/C gene polymorphism with susceptibility to end-stage renal disease. Immunogenetics. 2007;59:159-65 pubmed..Further, combined analysis implicated a higher risk in ESRD patients with low IL-4 and high IL-6 producing genotypes. This study provided the basis for defined anti-inflammatory approaches to limit renal disease progression. ..
- Levin A, Bates D, Ring A, Krieg C, Lin J, Su L, et al. Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature. 2012;484:529-33 pubmed publisher..Collectively, we show that in vitro evolution has mimicked the functional role of CD25 in enhancing IL-2 potency and regulating target cell specificity, which has implications for immunotherapy. ..
- Smyth D, Plagnol V, Walker N, Cooper J, Downes K, Yang J, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359:2767-77 pubmed publisher..These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases. ..
- Pei Y, Zhu P, Dang Y, Wu J, Yang X, Wan B, et al. Nuclear export of NF90 to stabilize IL-2 mRNA is mediated by AKT-dependent phosphorylation at Ser647 in response to CD28 costimulation. J Immunol. 2008;180:222-9 pubmed..In vivo and in vitro data support a model in which CD28 costimulation activates AKT to phosphorylate NF90 at Ser647 and phosphorylation triggers NF90 to relocate to the cytoplasm and stabilize IL-2 mRNA. ..
- van Heel D, Franke L, Hunt K, Gwilliam R, Zhernakova A, Inouye M, et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet. 2007;39:827-9 pubmed..3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease. ..
- Wu H, Chang C, Wan L, Wu C, Tsai F, Chen W. IL-2 gene C/T polymorphism is associated with prostate cancer. J Clin Lab Anal. 2006;20:245-9 pubmed..388). This study suggests that the IL-2 gene may be associated with susceptibility to prostate cancer in the Taiwan population. ..
- Thanos C, DeLano W, Wells J. Hot-spot mimicry of a cytokine receptor by a small molecule. Proc Natl Acad Sci U S A. 2006;103:15422-7 pubmed..Our studies suggest that precise structural mimics of receptors are not required for high-affinity binding of small molecules, and they show that there are multiple solutions to tight binding at shared and adaptive hot spots. ..
- Kreisberg J, Yonemoto W, Greene W. Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation. J Exp Med. 2006;203:865-70 pubmed
- Festen E, Goyette P, Scott R, Annese V, Zhernakova A, Lian J, et al. Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut. 2009;58:799-804 pubmed publisher..type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD...
- Teixeira V, Pierlot C, Migliorini P, Balsa A, Westhovens R, Barrera P, et al. Testing for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in a European family-based study. Arthritis Res Ther. 2009;11:R45 pubmed publisher..Further investigation of this region, including detection and testing of all variants, is required to confirm rheumatoid arthritis association. ..
- Campos M, Godoy dos Santos M, Trevilatto P, Scarel Caminaga R, Bezerra F, Line S. Interleukin-2 and interleukin-6 gene promoter polymorphisms, and early failure of dental implants. Implant Dent. 2005;14:391-6 pubmed
- Hunt K, Zhernakova A, Turner G, Heap G, Franke L, Bruinenberg M, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. 2008;40:395-402 pubmed publisher..Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways. ..
- Romanos J, Barisani D, Trynka G, Zhernakova A, Bardella M, Wijmenga C. Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease. J Med Genet. 2009;46:60-3 pubmed publisher..Our results may imply there is a genuine population difference across Europe regarding the loci contributing to CD. ..
- Berković M, Jokic M, Marout J, Radosevic S, Zjacic Rotkvic V, Kapitanovic S. IL-2 -330 T/G SNP and serum values-potential new tumor markers in neuroendocrine tumors of the gastrointestinal tract and pancreas (GEP-NETs). J Mol Med (Berl). 2010;88:423-9 pubmed publisher..039). Compared to CgA and 5-HIAA, IL-2 was more specific in detecting GEP-NET patients (p < 0.0001 and p < 0.0001, respectively). Our results indicate importance of IL-2 in GEP-NET development and biochemical diagnosis. ..
- Coenen M, Trynka G, Heskamp S, Franke B, van Diemen C, Smolonska J, et al. Common and different genetic background for rheumatoid arthritis and coeliac disease. Hum Mol Genet. 2009;18:4195-203 pubmed publisher..We confirmed two known loci and identified four novel ones for shared CD-RA genetic risk. Most of the shared loci further emphasize a role for adaptive and innate immunity in these diseases. ..
- Millan O, Rafael Valdivia L, Torrademé E, Lopez A, Fortuna V, Sánchez Cabús S, et al. Intracellular IFN-? and IL-2 expression monitoring as surrogate markers of the risk of acute rejection and personal drug response in de novo liver transplant recipients. Cytokine. 2013;61:556-64 pubmed publisher..Therefore, effector-T-cell response monitoring may help physicians to identify personal response to treatment and patients at high risk of AR. ..
- Cavanillas M, Alcina A, Nunez C, De las Heras V, Fernandez Arquero M, Bartolome M, et al. Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk. Eur J Hum Genet. 2010;18:794-9 pubmed publisher..The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation. ..
- Goudy K, Johnson M, Garland A, Li C, Samulski R, Wang B, et al. Inducible adeno-associated virus-mediated IL-2 gene therapy prevents autoimmune diabetes. J Immunol. 2011;186:3779-86 pubmed publisher..These results demonstrate that inducible IL-2 gene therapy is an effective and safe approach to manipulate Foxp3(+)Treg and suppress T cell-mediated autoimmunity and that under the conditions employed, IL-2 is more potent than TGF-?1. ..
- Warren R, Smith R, Flynn E, Bowes J, Eyre S, Worthington J, et al. A systematic investigation of confirmed autoimmune loci in early-onset psoriasis reveals an association with IL2/IL21. Br J Dermatol. 2011;164:660-4 pubmed publisher..The findings, although requiring replication, suggest that IL2/IL21 may play a key role in the pathogenesis of psoriasis as well as in other diverse autoimmune diseases. ..
- Park S, Yoon Y, Kang S, Kim T, Kim Y, Joo H, et al. Impact of IL2 and IL2RB genetic polymorphisms in kidney transplantation. Transplant Proc. 2011;43:2383-7 pubmed publisher..738; P = .0295) showed associations with ARE. Our results demonstrate that genetic variants of IL2RB may be associated with the development of AREs and may help predict ARE risk in kidney transplantation patients. ..
- Rani A, Afzali B, Kelly A, Tewolde Berhan L, Hackett M, Kanhere A, et al. IL-2 regulates expression of C-MAF in human CD4 T cells. J Immunol. 2011;187:3721-9 pubmed publisher..Thus, our findings demonstrate the importance of IL-2 in Th2 differentiation in human T cells and support the notion that IL-2R-directed therapies may have utility in the treatment of allergic disorders. ..
- Liao W, Lin J, Leonard W. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr Opin Immunol. 2011;23:598-604 pubmed publisher..In this fashion, IL-2 can prime and potentially maintain Th1 and Th2 differentiation as well as expand such populations of cells, whereas it inhibits Th17 differentiation but also can expand Th17 cells. ..
- Zou T, Satake A, Corbo Rodgers E, Schmidt A, Farrar M, Maltzman J, et al. Cutting edge: IL-2 signals determine the degree of TCR signaling necessary to support regulatory T cell proliferation in vivo. J Immunol. 2012;189:28-32 pubmed publisher..These findings also have therapeutic implications, as TCR signaling by Tregs may not be required when using IL-2 to increase Treg numbers for treatment of inflammatory disorders. ..
- Song N, Han S, Lee K, Choi J, Park S, Jeon S, et al. Genetic variants in interleukin-2 and risk of lymphoma among children in Korea. Asian Pac J Cancer Prev. 2012;13:621-3 pubmed..TT=3.43 (1.29-9.11), P(trend)=0.002, minP=0.005). These findings suggest that common genetic variants in IL2 might play a role in the pathogenesis of childhood lymphoma. ..
- Castro I, Yu A, Dee M, Malek T. The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development. J Immunol. 2011;187:5170-82 pubmed publisher..Our findings are consistent with a model whereby low, intermediate, and high CD122 signaling support T(CM) memory survival, T(EM) programming, and terminal T effector cell differentiation, respectively. ..
- Sester U, Fousse M, Dirks J, Mack U, Prasse A, Singh M, et al. Whole-blood flow-cytometric analysis of antigen-specific CD4 T-cell cytokine profiles distinguishes active tuberculosis from non-active states. PLoS ONE. 2011;6:e17813 pubmed publisher..In conclusion, a frequency lower than 56% IFN-?/IL-2 dual positive PPD-specific circulating CD4 T-cells is strongly indicative of active TB. ..
- Neri F, Giolo G, Potestà M, Petrini S, Doria M. The HIV-1 Nef protein has a dual role in T cell receptor signaling in infected CD4+ T lymphocytes. Virology. 2011;410:316-26 pubmed publisher..Our data indicate that Nef has a dual role in the modulation of TCR signaling aimed at favoring HIV-1 replication and spread in both quiescent and metabolically active CD4(+) T lymphocytes. ..
- Daha N, Kurreeman F, Marques R, Stoeken Rijsbergen G, Verduijn W, Huizinga T, et al. Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis. Arthritis Rheum. 2009;60:1255-60 pubmed publisher..Given the strong statistical power of our meta-analysis to confirm a true-positive association, these findings provide considerable support for the involvement of CTLA4 in distinct subsets of RA patients. ..
- Javor J, Bucova M, Ferencik S, Grosse Wilde H, Buc M. Single nucleotide polymorphisms of cytokine genes in the healthy Slovak population. Int J Immunogenet. 2007;34:273-80 pubmed..However, several differences were found between the Slovak and four populations from Southern Europe. The obtained data represent a basis for further studies on association of cytokine gene polymorphisms with some diseases. ..
- Fedetz M, Ndagire D, Fernandez O, Leyva L, Guerrero M, Arnal C, et al. Multiple sclerosis association study with the TENR-IL2-IL21 region in a Spanish population. Tissue Antigens. 2009;74:244-7 pubmed publisher..Additional studies, using much larger sample sizes and analysis of additional polymorphisms in the gene and its flanking region, will be required to ascertain their contributions to MS susceptibility. ..
- Lindemann M, Hu Z, Benczik M, Liu K, Gaffen S. Differential regulation of the IL-17 receptor by gammac cytokines: inhibitory signaling by the phosphatidylinositol 3-kinase pathway. J Biol Chem. 2008;283:14100-8 pubmed publisher..Thus, there are intrinsic signaling differences between IL-2 and IL-15 that can be attributed to differences in activation of the PI3K pathway. ..
- Scola L, Candore G, Colonna Romano G, Crivello A, Forte G, Paolisso G, et al. Study of the association with -330T/G IL-2 in a population of centenarians from centre and south Italy. Biogerontology. 2005;6:425-9 pubmed..All in all our data seem to suggest that reduction of -330G allele frequency might be protective for healthy ageing limiting cell mediated inflammation implied in age associated diseases. ..
- Stauber D, Debler E, Horton P, Smith K, Wilson I. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006;103:2788-93 pubmed..The IL-2/gamma(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes. ..
- Wang X, Rickert M, Garcia K. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science. 2005;310:1159-63 pubmed..This complex structure provides a framework for other gammac-dependent cytokine-receptor interactions and for the engineering of improved IL-2 therapeutics. ..
- Kryworuchko M, Pasquier V, Theze J. Human immunodeficiency virus-1 envelope glycoproteins and anti-CD4 antibodies inhibit interleukin-2-induced Jak/STAT signalling in human CD4 T lymphocytes. Clin Exp Immunol. 2003;131:422-7 pubmed..This Jak/STAT deficiency may contribute to the crippling of CD4 T cell responses to a cytokine central to the immune response by HIV. ..
- McDaniel D, Barber W, Nguyan C, Rhodes S, May W, McDaniel L, et al. Combined analysis of cytokine genotype polymorphism and the level of expression with allograft function in African-American renal transplant patients. Transpl Immunol. 2003;11:107-19 pubmed..Identification of peripheral markers diagnostic of rejection could allow advance anticipation of clinical outcome, and might reduce the need for tissue biopsy. ..
- Holweg C, Peeters A, Balk A, Uitterlinden A, Niesters H, Maat A, et al. Recipient gene polymorphisms in the Th-1 cytokines IL-2 and IFN-gamma in relation to acute rejection and graft vascular disease after clinical heart transplantation. Transpl Immunol. 2003;11:121-7 pubmed..63). In conclusion, we did not detect an association between the IL-2 T-330G promoter polymorphism and CA repeat polymorphism in the first intron of the IFN-gamma gene and AR or GVD after heart transplantation. ..
- Zurawski S, Vega F, Doyle E, Huyghe B, Flaherty K, McKay D, et al. Definition and spatial location of mouse interleukin-2 residues that interact with its heterotrimeric receptor. EMBO J. 1993;12:5113-9 pubmed..The relative spatial locations of these three surfaces are different from the two receptor binding sites known for the structurally related human growth hormone and the significance of this observation is discussed. ..
- Matesanz F, Fedetz M, Leyva L, Delgado C, Fernandez O, Alcina A. Effects of the multiple sclerosis associated -330 promoter polymorphism in IL2 allelic expression. J Neuroimmunol. 2004;148:212-7 pubmed..Our data show an increased IL2 expression among GT and TT genotypes previously associated with susceptibility to MS. ..
- Devireddy L, Green M. Transcriptional program of apoptosis induction following interleukin 2 deprivation: identification of RC3, a calcium/calmodulin binding protein, as a novel proapoptotic factor. Mol Cell Biol. 2003;23:4532-41 pubmed..This process is regulated, at least in part, by the cytokine interleukin 2 (IL-2): T cells deprived of IL-2 undergo apoptosis...
- Fedetz M, Matesanz F, Caliz R, Ferrer M, Collado M, Alcina A, et al. Lack of association between -384 and 114 IL-2 gene polymorphisms and rheumatoid arthritis. J Rheumatol. 2003;30:435-7 pubmed..To investigate the association of 2 single nucleotide polymorphisms (SNP) at positions -384 and 114 in the human interleukin 2 (IL-2) gene with susceptibility to and severity of rheumatoid arthritis (RA)...
- Pawlik A, Domanski L, Rozanski J, Florczak M, Dabrowska Zamojcin E, Dutkiewicz G, et al. IL-2 and TNF-alpha promoter polymorphisms in patients with acute kidney graft rejection. Transplant Proc. 2005;37:2041-3 pubmed..The results suggest that TNF-alpha-308 promoter polymorphism is a risk factor for acute kidney allograft rejection. ..
- Attema J, Reeves R, Murray V, Levichkin I, Temple M, Tremethick D, et al. The human IL-2 gene promoter can assemble a positioned nucleosome that becomes remodeled upon T cell activation. J Immunol. 2002;169:2466-76 pubmed
- Cox E, Hoffmann S, DiMercurio B, Wesley R, Harlan D, Kirk A, et al. Cytokine polymorphic analyses indicate ethnic differences in the allelic distribution of interleukin-2 and interleukin-6. Transplantation. 2001;72:720-6 pubmed..These findings may have relevance in making prognostic determinations or tailoring immunomodulatory regimens after renal transplantation. ..
- Wang J, Kiyokawa E, Verdin E, Trono D. The Nef protein of HIV-1 associates with rafts and primes T cells for activation. Proc Natl Acad Sci U S A. 2000;97:394-9 pubmed..Overall, these data suggest that Nef acts at the level of rafts to prime T cells for activation. Likely consequences of this effect are the promotion of HIV-1 replication and the facilitation of virus spread. ..
- Glushakova S, Grivel J, Suryanarayana K, Meylan P, Lifson J, Desrosiers R, et al. Nef enhances human immunodeficiency virus replication and responsiveness to interleukin-2 in human lymphoid tissue ex vivo. J Virol. 1999;73:3968-74 pubmed..Thus, Nef can facilitate HIV-1 replication in human lymphoid tissue ex vivo by increasing the numbers of productively infected cells and by increasing the responsiveness to IL-2 stimulation. ..
- Minami Y, Kono T, Miyazaki T, Taniguchi T. The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol. 1993;11:245-68 pubmed..Another pathway leads to c-myc gene induction by an as yet unknown mechanism. We discuss the complex signalling machinery that links the cell surface receptor to the nuclear events. ..
- Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature. 1991;352:621-4 pubmed
- Bayley J, Bakker A, Kaijzel E, Wierenga E, van der Pouw Kraan T, Huizinga T, et al. Analysis of allelic expression patterns of IL-2, IL-3, IL-4, and IL-13 in human CD4+ T cell clones. Eur J Immunol. 2003;33:2142-8 pubmed..The gene for IL-4 showed an imbalance in expression from each allele, indicating differential expression of IL-4 alleles within or between IL-4-expressing cells. ..
- Bamborough P, Hedgecock C, Richards W. The interleukin-2 and interleukin-4 receptors studied by molecular modelling. Structure. 1994;2:839-51 pubmed..In addition, they may be of use in the identification of residues which may interact in the ligand-receptor interfaces, and which would therefore be worthy of further investigation. ..
- Sadlack B, Merz H, Schorle H, Schimpl A, Feller A, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993;75:253-61 pubmed..The data provide evidence for a primary role of the immune system in the etiology of ulcerative colitis and strongly suggest that the disease results from an abnormal immune response to a normal antigenic stimulus. ..
- Matesanz F, Delgado C, Fresno M, Alcina A. Allelic selection of human IL-2 gene. Eur J Immunol. 2000;30:3516-21 pubmed..These findings may be used as a suitable marker for monitoring the IL-2 allelic contribution to effector activities and in immune responses against different infections or in pathological situations. ..
- Matesanz F, Fedetz M, Collado Romero M, Fernandez O, Guerrero M, Delgado C, et al. Allelic expression and interleukin-2 polymorphisms in multiple sclerosis. J Neuroimmunol. 2001;119:101-5 pubmed..These data indicate for the first time the relevance of the il-2 gene locus in human MS and its possible involvement in other autoimmune diseases. ..
- Pawlik A, Domanski L, Rozanski J, Florczak M, Wrzesniewska J, Dutkiewicz G, et al. The cytokine gene polymorphisms in patients with chronic kidney graft rejection. Transpl Immunol. 2005;14:49-52 pubmed..The results of present study suggest that the genetically determined low IL-6 production may be the risk factor of chronic allograft nephropathy development. ..
- Zheng S, Wang J, Gray J, Soucier H, Horwitz D. Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol. 2004;172:5213-21 pubmed..We suggest that the long-term effects of adoptively transferred natural-like CD4(+)CD25(+) regulatory cells induced ex vivo are due to their ability to generate new cytokine-producing CD4(+) regulatory T cells in vivo. ..