EVAN Naive CD8 T cells differentiate into protective memorylike cel - PDF document

EVAN. Naive CD8+ T cells differ-entiate into protective memorylike cells after IL-2anti IL-2 complex treatment in vivo. J Exp Med2007; 204: 1803-1812.VANEM, KARTINANTALEOG, SJ, S. IL-2/an-ti-IL-2 antibody complexes show strong biologicalactivity by avoiding interaction with IL-2 receptoralpha subunit CD25. Proc Natl Acad Sci USA2010; 107: 2171-2176R, ZAVAA, CAMPAGNOLOL, S. Expansion of regulatory T cells viaIL-2/anti-IL-2 mAb complexes suppresses experi-mental myasthenia. Eur J Immunol 2010; 40:S, PANTALEOG, B. Im-proved IL-2 immunotherapy by selective stimula-tion of IL-2 receptors on lymphocytes and en-dothelial cells. Proc Natl Acad Sci USA 2010;107: 11906-11911. Y, FL, L. Rapamycin in combination with donor-spe-cific CD4+CD25+Treg cells amplified in vitro mightbe realize the immune tolerance in clinical organtransplantation. Cell Immunol 2010; 264: 111-113. L, CM, SM, MANDAPATHIL. Differential responses of human reg-ulatory T cells and effector T cells to rapamycin.PLoS One 2009; 4: 5994.P, SM, MP, PL, SONIFACIOE, RATTAGLIA. Ra-pamycin monotherapy in patients with type 1diabetes modifies CD4+CD25+FOXP3+ regula-tory T-cells. Diabetes 2008; 57: 2341-2347.Combination of rapamycinand IL-2 increases de novo induction of humanCD4+CD25+ FOXP3+T cells. J Autoimmun 2008;30: 293-302.H, A. Revisting the role of IL-2. Re-visting the role of IL-2 in autoimmunity. Eur J im-munol 2010; 40: 1538-1540.X, BS, JLT, BPlasticity of CD4+FoxP3+T cells. Curr Opin Im-munol 2009; 21: 281-285.E, MM, KH, PORCHERAYF, LR, CLYEAEP, SCombined CD4+ donor lymphocyte infusion andlow-dose recombinant IL-2 expand FOXP3+ regu-latory T cells following allogeneic hematopoieticstem cell transplantation. Biol Blood MarrowTransplant 2009; 15: 382-388.JL, JHuman T regulatorycell therapy: take a billion or so and call me in themorning. Immunity 2009; 30: 656-665. Interleukin-2 and autoimmune disease occurrence and therapy I, ZM, FM, SThe interleukin-2-deficient mouse model.Pathobiology 2003; 70: 139-142.R, HS, TT, SHomeostatic maintenance of natural Foxp3(+)CD25(+) CD4(+) regulatory T cells by inter-leukin (IL)-2 and induction of autoimmune dis-ease by IL-2 neutralization. J Exp Med 2005;201: 723-735. JP, GAVINAY.A function for interleukin-2 in Foxp3-expressingregulatory T cells. Nat Immunol 2005; 6: 1142-E, BM, OOYA. FOXP3 forkhead do-main mutation and regulatory T cells in theIPEX syndrome. N Engl J Med 2009; 361:1710-1713.Development and function ofagonist-induced CD25+Foxp3+ regulatory T cellsin the absence of interleukin 2 signaling. Nat Im-munol 2005; 6: 1152-1159, HATTARM, CW, S. Expanding andconverting regulatory T cells: a horizon for im-munotherapy. Arch Immunol Ther Exp (Warsz)2009; 57: 199-204.AYERAL, YA, Arole for interleukin-2 for CD4+CD 25+ T regulato-ry cell development during the neonatal period. JExp Med 2005; 5: 769-777.A, ZL, ALTMAN. A low inter-leukin-2 receptor signaling threshold supports thedevelopment and homeostasis of T regulatorycells. Immunity 2009; 30: 204-217.J, WKC, DEBATINAutocrine T-cell suicide mediatedby APO-1/(Fas/CD95). Nature 1995; 373: 438-A, WM, KBT, LThe role of the common cytokine receptor chainin regulating IL-2-dependent, activation-in-duced CD8+ T cell death. J Immunol 1999; 163:L, ZL, YY, KHK, DATTA. Human lu-pus T cells resist inactivation and escape deathby upregulating COX-2. Nat Med 2004; 10: 411-415. ficiency. Pediatr Res 2000; 48: 6-11.F, LEVANInterleukin-2 and inflamma-tion induce distinct transcriptional programs thatpromote the differentiation of effector cytolytic Tcells. Immunity 2010; 32: 79-90.ORTER

P, YNormal lymphoid homeostasis and lack of lethalautoimmunity in mice containing mature Tcellswith severely impaired IL-2 receptors. J Immunol2000; 164: 2905-2914.UINTARELLIAVOLDO. Gene therapyto improve function of T cells for adoptive im-munotherapy. Methods Mol Biol 2010; 651: 119-J, KERSTANNKW, AM, LYF, G. Modulation by IL-2 of CD70and CD27 expression on CD8+ T cells: impor-tance for the therapeutic effectiveness of celltransfer immunotherapy. J Immunol 2006; 176:AF, RPM, G. CD27expression promotes long-termsurvival of func-tional effector memory CD8+ cytotoxic T lympho-cytes in HIV-infected patients. J Exp Med 2004;200: 1407-1417.V, XY, V. CD27sustains survival of CTLs in virus-infected non-lymphoid tissue in mice by inducing autocrineIL-2 production. J Clin Invest 2010; 120: 168-S, CK, SABZEVARI. IL-2/anti-IL-2antibody complex enhances vaccine-mediatedantigen-specific CD8+T cell responses and in-creases the ratio of effector/memory CD8+Tcells to regulatory T cells. J Immunol 2008; 180:Y, LA, CJ, EMERYS, FL, GITSUYASUR, NEATONA, RJP, TG, WENTWORTH. In-terleukin-2 therapy in patients with HIV infection.N Engl J Med 2009; 361: 1548-1559.E, KM, PIL-2 as atherapeutic target for the restoration of Foxp3+regulatory T cell function in organ-specific au-toimmunity: implications in pathophysiology andtranslation to human disease. J Transl Med 2010;8: 113. E, NM, PORCHERAYF, KH, LR, RE, CIL-2 regulates FOXP3expression in human CD4+CD25+ regulatory Tcells through a STAT-dependent mechanism andinduces the expansion of these cells in vivo.Blood 2006; 108: 1571-1579.JY, PK, PE, P. Central role of defective interleukin-2 produc-tion in the triggering of islet autoimmune destruc-tion. Immunity 2008; 28: 687-697.Potential use ofIL-2/anti-IL-2 antibody immune complexes forthe treatment of cancer and autoimmune dis-ease. Expert Opin Biol Ther 2006; 6: 1323-OVARM, RMP, SSelective stimulation of T cell subsetswith antibody-cytokine immune complexes. Sci-ence 2006; 311: 1924-1927.X. Geng, R. Zhang, G. Yang, W. Jiang, C. Xu sive drug but also is a kind of proliferation signally, then combine with the intracellular im-munophilinFK506-binding protein (FKBP12),complex which targets IL-2 to downstreammTOR,and inhibits proliferation of effector T. Previous experiments showed that Tregcells responded to rapamycin differently from Teffector (Teff)cells. After treated with ra-pamycin, Treg cells could up-regulate anti-apop-totic molecules, and down-regulate pro-apoptoticmolecules and then the balance between Tregcell and effector T cellswas altered. It was re-cently showed that rapamycin was not only ableto increase Treg cells, but also improvetheirspeciÞc suppressive capability against effector Tin vivo. Therefore, these findingspromot-ed the application of the therapy combining IL-2with rapamycin. In humans, treating CD4+ Tcells with both IL-2 and rapamycin in vitro led toan increase in the number of FOXP3+ T cellsIn addition, this kind of combination therapywith IL-2 to increase the number of Treg and im-prove its function, and mTOR inhibitors to blockthe generation of effector T cells, proved to bebeneficial in curing immunological disordersGenerally, cell therapy is very promising. To ob-tain sufficient Treg cells is a major challenge intreating autoimmune diseases, due to the very lowabundance of Treg cells. Therefore, proliferationand differentiation of Treg cells in vitrowas recent-ly the focus of clinical trials. Moreover, researchershave highlighted that the instability and hetero-geneity of Treg cells is also a major problem in cel

ltherapy. In addition, the loss of function of mas-sively injected Treg population and their subse-quent likely conversion into pathogenic T cellsthrows doubt upon the future of Treg immunother-apy. Fortunately, IL-2 can stabilize the function ofFOXP3+ Treg cells, so IL-2 therapy in combina-tion with Treg infusion can represent a plausible al-ternative. Indeed, the combination of low doseIL-2 with Treg infusion can significantly improvethe medical effect of HSCT by increasing the num-ber of Treg cells invivothat it was possible to use clinical-grade lentiviralvectors to redirect Treg cells to the target cells, andto prevent Treg cells from converting into effectorT cells, which kept the infused Treg cells express-ing Foxp3.IL-2 signal plays a key role in promoting de-velopment, homeostasis and function of regulato-ry T cells. IL-2 affects multiple signal pathways,and its deficiency causes the multifacted dysreg-ulation of immune response. The decreased pro-duction of IL-2 in patients with autoimmune dis-ease triggers various immune defects, such as de-creased production of Treg cells, decreasedAICD and decreased cytotoxicity of CTL. Thedecreased cytotoxicity of CTL would make pa-tients more susceptible to intracellular infection.Therefore, to ensure the amount and function ofIL-2 may help to realize the potential of IL-2 asan immunotherapeutic effect and ensure clinicalThanks should be given to the National Basic Re-search 973 Pre-research Program of China, No.References. Novel molecular targets inthe treatment of systemic lupus erythematosus.Autoimmune Rev 2008; 7: 256-261.Y, KT, MIYAZAKIT, T. The IL-2 receptor complex: Its structure, function, andtarget genes. Annu Rev Immunol 1993; 11: 245-Y, RM, FY, AHeterodimerization of the IL-2 re-ceptor beta- and gamma-chain cytoplasmic do-mains is required for signalling. Nature 1994;369: 330-333.J, FERRYJA, DAVIDSONL, MA, AFW.Interleukin-2 receptor alpha chainregulates the size and content of the peripherallymphoid compartment. Immunity 1995; 3: 521-The biology of interleukin-2. Annu RevImmunol 2008; 26: 453-479. S, KANTALEOG, B. IL-2-and CD25-dependent immunoregulatory mech-anisms in the homeostasis of T-cell subsets. J Al-lergy Clin Immunol 2009; 123: 758–762. . Interleukin-2: Inception, impact, and im-plications. Science 1988; 240: 1169-1176JJ, GM, Snaling in 2002: new surprises in the Jak/Statpathway. Cell 2002; 109: S121-131. Interleukin-2 and autoimmune disease occurrence and therapy X. Geng, R. Zhang, G. Yang, W. Jiang, C. Xuic myelogenousleukemia after allogeneicit was showed that low-dose IL-2 treatment re-sulted in a 1.9 median fold increasein the num-ber of CD4+CD25+ cells in peripheral blood aswellas a 9.7 median fold increase in FOXP3ex-pression in CD3+Tcells, and that this effectseemingly increased as the treatment wentMoreover, it has been proved that a low-dose IL-2 treatment promoted Treg cell survival andpre-vented diabetes occurrence in NOD miceAt first, researchers treated cancer with highdoses of IL-2, but the short half-life of purifiedIL-2and the high toxic of high-dose IL-2 limitedits application in cancer treatmentin recent years, scientists adopted the combina-tion of IL-2 with a carrier protein, such as bovineserum albumin (BSA), gelatin or even an irrele-vant immunoglobulin chain, which have success-fully prolonged the half-life of IL-2 and reducedits side effectsIt has been pointed out that treating cancerwith Treg cells did not work well. Subsequently,a new therapy method came into being, that is,IL-2 was coupled with different anti-IL-2 mono-cl

onal antibodies (mAb) and then preferentiallyacted on CD25 or CD122 by varying the mAb,which is specific and effective in treating au-toimmune disease. Recently, it was demon-strated that IL-2/ mAbcomplex treatmentproduced 40-fold effect than soluble IL-2 treat-ment did;after the half-life of IL-2 was pro-longed and the interaction of IL-2 with CD25was blockedpointed out that anti-IL-2-IL-2 complex could cure autoantibody-depen-dent disease via proliferation of Treg cellsMeanwhile, IL-2 and Anti-IL-2 complexanti-IL-2-IL-2 complex could activate IL-2R fector T cell, which honored a powerful anti-tu-mor effect to effector T cell. Therefore, the com-plex might improve tumor immune therapeuticstrategiesbased on IL-2At present, another way to efficiently treat au-toimmune disease with IL-2 is to selectively tar-get IL-2 to Treg cells by using specific medica-tion to selectively modulate biochemical path-ways in Treg cells or effector T cells. Rapamycinis not only a kind of common immunosuppres-Cytotoxic Tlymphocyte (CTL)developmentwas decreased with the absence of IL-2, whichindicated that IL-2 is necessary for the develop-ment of CD8+ T cell and NK cell cytoxicity.Moreover, it is significant for these cell types toÞght infection and for cytotoxic T lymphocytes(CTLs) cells to destruct virally infected cells andintracellular parasitic pathogen-infected targetcells. One research showed that IL-2 up-regulat-ed perforin transcription, and suppressed re-ex-pression of memory CTL markers Bcl6 and IL-. However, in mice infected by lymphocyticchoriomeningitis virus, -deficient effectorCD8+T cells up-regulated Bcl6 and down-regu-lated perforin and granzymeB, the hallmarks ofCD8+ T cell cytotoxicity, leading to decreasedCTL. Thus, inflammation influences differentia-tion of effector and memory CTL, whereas per-sistent stimulation of IL-2 promotes generationof effector CTL at the expense of memory CTLdevelopment. Transgenic expression of IL-2could increase the expansion of CTLsresearch demonstrated that IL-2 up-regulated thecostimulatory molecule CD70 which was neces-sary for expansion of CD8+T cells. When CD70was blocked, CTL expansion did not occurCD8+T cells could express costimulatory mole-cule CD27 and preferentially secrete IL-2cently, it has been found that IL-2 production in-duced by CD27 stimulates the survival of CD8+T cell in an autocrine manner in virally infected. In addition, some researchers treatedmice with IL-2 complex, and found that CTL ef-fect was enhanced in . These evidencesprove that IL-2 signal necessary for the devel-opment of cytotoxicity.Il-2 and The Therapy of IL-2 has strong proliferative effects on T cells,and was firstly used as a therapeutic approach toboost immune responses in patients with invasivecancer or advanced HIV diseaseTreg cells were capable of forming the highestaffinity receptor complex for IL-2, due to theirconstitutive expression of CD25. Hence, they be-came sensitive to very low level of IL-2,whichsupported the rationale of examining the poten-tial of low-dose IL-2 for ÒTreg-only enhancing. In the study on patients with chron- 1464 eases and other autoimmune diseases.Further re-search showed that the deletion of IL-2 causedthe lack of CD4+CD25+regulatory T cells,which resulted in the occurrence of T-cell medi-The research on-deficient mice showedthat long-term lack of IL-2 signal resulted in anexcessive proliferation of autoreactive T lympho-cytes, further the occurrence of autoimmune dis-Generally speaking, there are three types ofregulatory T cells (Treg cells): IL-10-induced Tr1-ind

uced Th3 cells and CD4+CD25+Treg. Treg cells with immunosuppressive proper-ties towards a variety of immune cells can inhibitT-cell proliferation, and they are characterizedwith preferential expression of Treg speciÞc tran-scription factor FOXP3 and constitutive expres-sion of IL-2RFOXP3sults in a decrease in the number of Treg cells,and the occurrence of multi-organ autoimmuni-. Meanwhile, Treg cells dependent on IL-2 in-by producing lymphatic regional signal. De-creased Treg cells leads to a lack of this kind ofsignal, the binding of IL-2 to low-affinity recep-tor and proliferation of autoreactive T cells, andfinally, autoimmune disease is caused.Decreasedbrings about a decrease in the number ofTreg cells and excessive lymphoproliferation,triggering the occurrence of autoimmunity. Thelow number of Treg cells in knockoutmice evidenced that Treg cells are not completelydependent on IL-2 for development. In addi-tion, the stable expression of FOXP3is criticalfor establishing and maintaining Treg lineageFOXP3 are completely short ofTreg cells and suffer from serious autoimmuneReportedly, mice with a lack of IL-2 or IL-2Rlacked CD4+CD25+Treg, while transgenic Tcells with insertedcould have a stable ex-pression of CD4+CD25+, keeping homeostasis,which showed that IL-2 played an important rolein preventing the occurrence of autoimmune dis-. Another research showed that -defi-cient CD4+CD25+Treg was not amplified in pe-ripheral lymphatic system of wild miceindicated that IL-2 was necessary for the amplifi-cation and development of CD25+CD4+Treggenerated by the thymus. If impaired IL-2R acti-vated Stat5in mice, a normal quantity of periph-eral Treg cells was generated. Meanwhile, thesemice wereprotected from lethal autoimmunitybut symptoms of organ-speciÞc autoimmunityoccurred to them as they aged. The findingsabove showed that the susceptibility that leads toautoimmune disease might increase, though thelow mount of IL-2R could maintain relativelynormal generation of Treg cells. In conclusion,deletion affects development, func-tion and homeostasis of Treg cells.After the activation of naive T cells by anti-genic stimulation through T-cell receptor (TCR),antigen specific T cells proliferated and differen-tiated into effector T cells, which eliminated anti-gen, then, the process of Activation-Induced CellDeath(AICD) destroyed the excess effector Tcells to maintain the balance among immunecells. IL-2 is required for this kind of controlledapoptotic mechanism, together with costimula-tion through CD95, tumor necrosis factor recep-tor 1 (TNFR1), and other costimulatory mole-Through up-regulating Fas ligand and TNFreceptor, down-regulating cysteine aspartic en-zyme inhibition factor (C-FLIP) and promotingthe synthesis of Interferon receptor (IFN-r), IL-2induced apoptosis of sensitized T cells. Howev-er, -deÞcient mice lacked the expres-sion of Interferon receptor (IFN-r), which blocksAICD. Furthermore, IL-2 in CD8+ T cells mod-ulated AICD by down-regulating IL-2Rceptor chain which was associated with cell sur-vival. Previous study showed that due to re-duced level of intracellular TNFand up-regula-tion of cyclooxygenase2(COX2), autoreactiveT cells lose regulatory role and become patho-splenomegaly. Consequently, systemic lupuserythematosus (SLE)patients were more resis-tant to AICD. Roifmanholds that in a patientwith mutation of IL-2Rproliferated and huge amounts of lymphocyticinfiltration of tissues was observed, in conjuc-tion with tissue atrophy and inflammation.-deficient thymocytes fails to down-regulatebcl-2,and subsequently,

apoptosis in the thymusis significantly reduced, leading to the expansionof autoreactive T cell and then the occurence of Interleukin-2 and autoimmune disease occurrence and therapy Review for 2), also called T-cell growth factor and primarilyproduced by antigen-activated T cells, is a kindof lymphoid factor with immunoregulatory effectwhich can promote T-cell-dependent immune re-sponses. IL-2 was first used as a therapeutic ap-proach to boost immune responses in patientswith invasive cancer or advanced HIV disease.The purpose of the review is torefer the mechanism of autoimmune diseasecaused by IL-2 deletion and the application of IL-2 in curing autoimmune disease. STATE OF THE ART:IL-2 signal plays a keyrole in promoting the development, homeostasisand the function of the regulatory T cells. Thedeletion of IL-2 autoimmune diseases. Now it is being consid-ered as a kind of medicine inhibiting immune re-Further studies with con-trolled clinical trials will be needed to prove thepotential of IL-2 as a therapeutic strategy for au-toimmune diseases.The decreased production ofIL-2 in patients with autoimmune disease leadsto immune defects, such as decreased produc-tion of Treg cells, decreased AICD and cytotoxic-ity. Combination therapy based on IL-2 mayprove to be beneficial in curing the immunologi-cal disorders.Interleukin-2 (IL-2), T-cell immune, Autoimmune dis- IntroductionInterleukin-2(IL-2), also named T-cell growthfactor, plays an important role in T cell biologyand can promote T-cell-dependent immune re-. IL-2is a kind of 4-bundle a-helical pro-tein with the molecular mass of 15 kDa. It is pri-marily produced by antigen-activated T cells and disease occurrence and therapy X. GENG, R. ZHANG, G. YANG, W. JIANG, C. XU*College of Life Science, Henan Normal University, Xinxiang, ChinaKey Laboratory for Cell Differentiation Regulation, Henan Province and ST Ministry, Xinxiang, China can bind to the high afÞnity receptor on targetcell membrane which consists of three subunits. Of them, IL-2Rplay an important role in transmiting intracellularcan increase the affinity of its re-ceptor by 10 to 100 folds, though not participat-ing in the signal transduction due to itÕs short cy-. Therefore, IL-2 does notproduce biological effects in solely binding to, but mediates the activation of target cellin binding to IL-2RcanÕt binds to IL-2singly, but is necessary for signal transductionsubunits.Moreover, high-affinity is constitutively ex-pressed in CD4+ regulatory T cells and in recent-ly antigen-activated T cells, while low-affinityis prominent on memory CD8+ T cells andNK cells. IL-2acts in an autocrine or paracrineway on these cells, many of which up-regulateCD25 expressionchains lack kinase activity,they canbe phosphorylated after binding to ki-nases JAK1 (Janus kinase gene 1) and JAK3.Then their SH2 domains recruit STAT5a/STAT5b. The later is phosphorylated by JAKsand translocated into nucleus as a heterodimericSTAT complex, which further regulates genetranscription by binding to target DNA. Other signaling pathways, such asMAPK and PI-3K, trigger signal transductionbyphosphorylating tyrosine residues within the cy-Barmeyerfound thatT cells and NKcells were present in newly-born mice with thedeletion of IL-2. Four weeks later, the hyperpla-sia of lymph node and intestinal lymphoid tissueand splenomegaly occurred, at the same time theconcentration of autoantibody in peripheralblood increased. Nine weeks later, 25%-50%mice died of severe hemolytic anemia, the otherssuffered from severe inflammatory bowel dis- 2012; 16: 1462-1