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Review

Role of IL-15 and IL-21 in viral immunity: applications for vaccines and therapies

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Pages 167-177 | Published online: 09 Jan 2014

References

  • Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the γc-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol. Rev.202, 67–83 (2004).
  • Demoulin JB, Renauld JC. Interleukin 9 and its receptor: an overview of structure and function. Int. Rev. Immunol.16(3–4), 345–364 (1998).
  • Radwanska M, Cutler AJ, Hoving JC et al. Deletion of IL-4Rα on CD4 T cells renders BALB/c mice resistant to Leishmania major infection. PLoS Pathog.3(5), E68 (2007).
  • Trigueros C, Hozumi K, Silva-Santos B et al. Pre-TCR signaling regulates IL-7 receptor α expression promoting thymocyte survival at the transition from the double-negative to double-positive stage. Eur. J. Immunol.33(7), 1968–1977 (2003).
  • Cao X, Shores EW, Hu-Li J et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity2(3), 223–238 (1995).
  • Combe CL, Moretto MM, Schwartzman JD et al. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite. Proc. Natl Acad. Sci. USA103(17), 6635–6640 (2006).
  • Cui FD, Asada H, Jin ML et al. Cytokine genetic adjuvant facilitates prophylactic intravascular DNA vaccine against acute and latent herpes simplex virus infection in mice. Gene Ther.12(2), 160–168 (2005).
  • Bolesta E, Kowalczyk A, Wierzbicki A et al. Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery. J. Immunol.177(1), 177–191 (2006).
  • Teague RM, Sather BD, Sacks JA et al. Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat. Med.12(3), 335–341 (2006).
  • Dooms H, Abbas AK. Control of CD4+ T-cell memory by cytokines and costimulators. Immunol. Rev.211, 23–38 (2006).
  • Yajima T, Nishimura H, Sad S et al. A novel role of IL-15 in early activation of memory CD8+ CTL after reinfection. J. Immunol.174(6), 3590–3597 (2005).
  • Kasaian MT, Whitters MJ, Carter LL 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. Immunity16(4), 559–569 (2002).
  • Becker TC, Wherry EJ, Boone D et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med.195(12), 1541–1548 (2002).
  • Surh CD, Boyman O, Purton JF, Sprent J. Homeostasis of memory T cells. Immunol. Rev.211, 154–163 (2006).
  • Bradley LM, Haynes L, Swain SL. IL-7: maintaining T-cell memory and achieving homeostasis. Trends Immunol.26(3), 172–176 (2005).
  • Osborne LC, Dhanji S, Snow JW et al. Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R α mutant mice. J. Exp. Med.204(3), 619–631 (2007).
  • Casey KA, Mescher MF. IL-21 promotes differentiation of naive CD8 T cells to a unique effector phenotype. J. Immunol.178(12), 7640–7648 (2007).
  • Alves NL, Arosa FA, van Lier RA. IL-21 sustains CD28 expression on IL-15-activated human naive CD8+ T cells. J. Immunol.175(2), 755–762 (2005).
  • Randall RE, Goodbourn S. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol.89(Pt 1), 1–47 (2008).
  • Walzer T, Dalod M, Vivier E, Zitvogel L. Natural killer cell-dendritic cell crosstalk in the initiation of immune responses. Expert Opin. Biol. Ther.5(Suppl. 1), S49–S59 (2005).
  • Howe RC, Dhiman N, Ovsyannikova IG, Poland GA. Induction of CD4 T cell proliferation and in vitro Th1-like cytokine responses to measles virus. Clin. Exp. Immunol.140(2), 333–342 (2005).
  • Boritz E, Palmer BE, Wilson CC. Human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T cells that proliferate in vitro detected in samples from most viremic subjects and inversely associated with plasma HIV-1 levels. J. Virol.78(22), 12638–12646 (2004).
  • Wong P, Pamer EG. CD8 T cell responses to infectious pathogens. Annu. Rev. Immunol.21, 29–70 (2003).
  • Boyman O, Purton JF, Surh CD, Sprent J. Cytokines and T-cell homeostasis. Curr. Opin. Immunol.19(3), 320–326 (2007).
  • Wilson CB, Marcuse EK. Vaccine safety – vaccine benefits: science and the public’s perception. Nat. Rev. Immunol.1(2), 160–165 (2001).
  • Mossman KL, Ashkar AA. Herpesviruses and the innate immune response. Viral Immunol.18(2), 267–281 (2005).
  • Brideau-Andersen AD, Huang X, Sun SC et al. Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases. Proc. Natl Acad. Sci. USA104(20), 8269–8274 (2007).
  • Gosselin J, TomoIu A, Gallo RC, Flamand L. Interleukin-15 as an activator of natural killer cell-mediated antiviral response. Blood94(12), 4210–4219 (1999).
  • Gill N, Ashkar AA. Adaptive immune responses fail to provide protection against genital HSV-2 infection in the absence of IL-15. Eur. J. Immunol.37(9), 2529–2538 (2007).
  • Purton JF, Tan JT, Rubinstein MP et al. Antiviral CD4+ memory T cells are IL-15 dependent. J. Exp. Med.204(4), 951–961 (2007).
  • Alves NL, Hooibrink B, Arosa FA, van Lier RA. IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro. Blood102(7), 2541–2546 (2003).
  • Kokaji AI, Hockley DL, Kane KP. IL-15 transpresentation augments CD8+ T cell activation and is required for optimal recall responses by central memory CD8+ T cells. J. Immunol.180(7), 4391–4401 (2008).
  • Brady J, Hayakawa Y, Smyth MJ, Nutt SL. IL-21 induces the functional maturation of murine NK cells. J. Immunol.172(4), 2048–2058 (2004).
  • Wang G, Tschoi M, Spolski R et al.In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res.63(24), 9016–9022 (2003).
  • Brandt K, Bulfone-Paus S, Foster DC, Ruckert R. Interleukin-21 inhibits dendritic cell activation and maturation. Blood102(12), 4090–4098 (2003).
  • Caprioli F, Sarra M, Caruso R et al. Autocrine regulation of IL-21 production in human T lymphocytes. J. Immunol.180(3), 1800–1807 (2008).
  • Kuchen S, Robbins R, Sims GP et al. Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell–B cell collaboration. J. Immunol.179(9), 5886–5896 (2007).
  • Allard EL, Hardy MP, Leignadier J et al. Overexpression of IL-21 promotes massive CD8+ memory T cell accumulation. Eur. J. Immunol.37(11), 3069–3077 (2007).
  • Ostiguy V, Allard EL, Marquis M, Leignadier J, Labrecque N. IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade. J. Leukoc. Biol.82(3), 645–656 (2007).
  • van Leeuwen EM, Gamadia LE, Baars PA et al. Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+T cells. J. Immunol.169(10), 5838–5843 (2002).
  • Ozaki K, Spolski R, Feng CG et al. A critical role for IL-21 in regulating immunoglobulin production. Science298(5598), 1630–1634 (2002).
  • Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol.6(8), 595–601 (2006).
  • Ma A, Koka R, Burkett P. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu. Rev. Immunol.24, 657–679 (2006).
  • Ohteki T, Tada H, Ishida K et al. Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo. J. Exp. Med.203(10), 2329–2338 (2006).
  • Burkett PR, Koka R, Chien M et al. Coordinate expression and trans presentation of interleukin (IL)-15Rα and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis. J. Exp. Med.200(7), 825–834 (2004).
  • Grabstein KH, Eisenman J, Shanebeck K et al. Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor. Science264(5161), 965–968 (1994).
  • Nishimura H, Yajima T, Naiki Y et al. Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo. J. Exp. Med.191(1), 157–170 (2000).
  • Tan X, Lefrancois L. Novel IL-15 isoforms generated by alternative splicing are expressed in the intestinal epithelium. Genes Immun.7(5), 407–416 (2006).
  • Nishimura H, Fujimoto A, Tamura N et al. A novel autoregulatory mechanism for transcriptional activation of the IL-15 gene by a nonsecretable isoform of IL-15 generated by alternative splicing. FASEB J.19(1), 19–28 (2005).
  • Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Rα recycles and presents IL-15 in trans to neighboring cells. Immunity17(5), 537–547 (2002).
  • Sato N, Patel HJ, Waldmann TA, Tagaya Y. The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc. Natl Acad. Sci. USA104(2), 588–593 (2007).
  • Kobayashi H, Dubois S, Sato N et al. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance. Blood105(2), 721–727 (2005).
  • Bulanova E, Budagian V, Duitman E et al. Soluble interleukin IL-15Rα is generated by alternative splicing or proteolytic cleavage and forms functional complexes with IL-15. J. Biol. Chem.282(18), 13167–13179 (2007).
  • Pasare C, Medzhitov R. Toll-dependent control mechanisms of CD4 T cell activation. Immunity21(5), 733–741 (2004).
  • Kobayashi N, Takesue M, Kobayashi N et al. Evaluation of Toll-like receptor 4 gene expression of immortalized human liver cell lines. Transplant. Proc.35(1), 431–432 (2003).
  • Coccia EM, Severa M, Giacomini E et al. Viral infection and Toll-like receptor agonists induce a differential expression of type I and λ interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur. J. Immunol.34(3), 796–805 (2004).
  • Hon H, Jacob J. Tracking dendritic cells in vivo: insights into DC biology and function. Immunol. Res.29(1–3), 69–80 (2004).
  • Kuwajima S, Sato T, Ishida K et al. Interleukin 15-dependent crosstalk between conventional and plasmacytoid dendritic cells is essential for CpG-induced immune activation. Nat. Immunol.7(7), 740–746 (2006).
  • Pulendran B. Division of labor and cooperation between dendritic cells. Nat. Immunol.7(7), 699–700 (2006).
  • Hultcrantz M, Huhn MH, Wolf M et al. Interferons induce an antiviral state in human pancreatic islet cells. Virology367(1), 92–101 (2007).
  • Andoniou CE, van Dommelen SL, Voigt V et al. Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat. Immunol.6(10), 1011–1019 (2005).
  • Huntington ND, Puthalakath H, Gunn P et al. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat. Immunol.8(8), 856–863 (2007).
  • Ashkar AA, Rosenthal KL. Interleukin-15 and natural killer and NKT cells play a critical role in innate protection against genital herpes simplex virus type 2 infection. J. Virol.77(18), 10168–10171 (2003).
  • Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity26(4), 503–517 (2007).
  • Liu G, Zhai Q, Schaffner D et al. IL-15 induces IFN-β and iNOS gene expression, and antiviral activity of murine macrophage RAW 264.7 cells. Immunol. Lett.91(2–3), 171–178 (2004).
  • Belyakov IM, Isakov D, Zhu Q et al. Enhancement of CD8+ T cell immunity in the lung by CpG oligodeoxynucleotides increases protective efficacy of a modified vaccinia Ankara vaccine against lethal poxvirus infection even in a CD4-deficient host. J. Immunol.177(9), 6336–6343 (2006).
  • Appay V, Douek DC, Price DA. CD8+ T cell efficacy in vaccination and disease. Nat. Med.14(6), 623–628 (2008).
  • Masopust D, Vezys V, Wherry EJ, Ahmed R. A brief history of CD8 T cells. Eur. J. Immunol.37(Suppl. 1), S103–S110 (2007).
  • Stemberger C, Neuenhahn M, Buchholz VR, Busch DH. Origin of CD8+ effector and memory T cell subsets. Cell. Mol. Immunol.4(6), 399–405 (2007).
  • Sandau MM, Winstead CJ, Jameson SC. IL-15 is required for sustained lymphopenia-driven proliferation and accumulation of CD8 T cells. J. Immunol.179(1), 120–125 (2007).
  • Yajima T, Yoshihara K, Nakazato K et al. IL-15 regulates CD8+T cell contraction during primary infection. J. Immunol.176(1), 507–515 (2006).
  • Wallace DL, Berard M, Soares MV et al. Prolonged exposure of naive CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length. Immunology119(2), 243–253 (2006).
  • Sauce D, Larsen M, Curnow SJ et al. EBV-associated mononucleosis leads to long-term global deficit in T-cell responsiveness to IL-15. Blood108(1), 11–18 (2006).
  • Virgin HW. Immune regulation of viral infection and vice versa. Immunol. Res.32(1–3), 293–315 (2005).
  • Oldstone MB. Viral persistence: parameters, mechanisms and future predictions. Virology344(1), 111–118 (2006).
  • Kohlmeier JE, Miller SC, Woodland DL. Cutting edge: antigen is not required for the activation and maintenance of virus-specific memory CD8+ T cells in the lung airways. J. Immunol.178(8), 4721–4725 (2007).
  • Khanna KM, Lepisto AJ, Decman V, Hendricks RL. Immune control of herpes simplex virus during latency. Curr. Opin. Immunol.16(4), 463–469 (2004).
  • Sheridan BS, Khanna KM, Frank GM, Hendricks RL. Latent virus influences the generation and maintenance of CD8+ T cell memory. J. Immunol.177(12), 8356–8364 (2006).
  • Wherry EJ, Ha SJ, Kaech SM et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity27(4), 670–684 (2007).
  • Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol.19(4), 408–415 (2007).
  • Wherry EJ, Barber DL, Kaech SM, Blattman JN, Ahmed R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl Acad. Sci. USA101(45), 16004–16009 (2004).
  • Parrish-Novak J, Dillon SR, Nelson A et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature408(6808), 57–63 (2000).
  • Coquet JM, Kyparissoudis K, Pellicci DG et al. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J. Immunol.178(5), 2827–2834 (2007).
  • Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. Cloning of a type I cytokine receptor most related to the IL-2 receptor β chain. Proc. Natl Acad. Sci. USA97(21), 11439–11444 (2000).
  • Distler JH, Jungel A, Kowal-Bielecka O et al. Expression of interleukin-21 receptor in epidermis from patients with systemic sclerosis. Arthritis Rheum.52(3), 856–864 (2005).
  • Jin H, Carrio R, Yu A, Malek TR. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J. Immunol.173(1), 657–665 (2004).
  • Sivori S, Cantoni C, Parolini S et al. IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors. Eur. J. Immunol.33(12), 3439–3447 (2003).
  • Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S. IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J. Immunol.169(7), 3600–3605 (2002).
  • Bettelli E, Korn T, Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr. Opin. Immunol.19(6), 652–657 (2007).
  • Reiner SL. Development in motion: helper T cells at work. Cell129(1), 33–36 (2007).
  • Wurster AL, Rodgers VL, Satoskar AR et al. Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon γ-producing Th1 cells. J. Exp. Med.196(7), 969–977 (2002).
  • Suto A, Wurster AL, Reiner SL, Grusby MJ. IL-21 inhibits IFN-γ production in developing Th1 cells through the repression of Eomesodermin expression. J. Immunol.177(6), 3721–3727 (2006).
  • Nurieva R, Yang XO, Martinez G et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature448(7152), 480–483 (2007).
  • Zeng R, Spolski R, Casas E et al. The molecular basis of IL-21-mediated proliferation. Blood109(10), 4135–4142 (2007).
  • White L, Krishnan S, Strbo N et al. Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV). Blood109(9), 3873–3880 (2007).
  • Spolski R, Leonard WJ. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol.26, 57–79 (2008).
  • Dou J, Tang Q, Zhao F et al. Comparison of immune responses induced in mice by vaccination with DNA vaccine constructs expressing mycobacterial antigen 85A and interleukin-21 and bacillus Calmette–Guerin. Immunol. Invest.37(2), 113–127 (2008).
  • Curtsinger JM, Johnson CM, Mescher MF. CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J. Immunol.171(10), 5165–5171 (2003).
  • Hernandez J, Aung S, Marquardt K, Sherman LA. Uncoupling of proliferative potential and gain of effector function by CD8+ T cells responding to self-antigens. J. Exp. Med.196(3), 323–333 (2002).
  • Sille FC, Visser A, Boes M. T cell priming by tissue-derived dendritic cells: new insights from recent murine studies. Cell. Immunol.237(2), 77–85 (2005).
  • Zeng R, Spolski R, Finkelstein SE et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med.201(1), 139–148 (2005).
  • Gagnon J, Ramanathan S, Leblanc C, Ilangumaran S. Regulation of IL-21 signaling by suppressor of cytokine signaling-1 (SOCS1) in CD8+ T lymphocytes. Cell. Signal.19(4), 806–816 (2007).
  • Luciano AA, Lederman MM, Valentin-Torres A, Bazdar DA, Sieg SF. Impaired induction of CD27 and CD28 predicts naive CD4 T cell proliferation defects in HIV disease. J. Immunol.179(6), 3543–3549 (2007).
  • Hendriks J, Gravestein LA, Tesselaar K et al. CD27 is required for generation and long-term maintenance of T cell immunity. Nat. Immunol.1(5), 433–440 (2000).
  • Gamadia LE, van Leeuwen EM, Remmerswaal EB et al. The size and phenotype of virus-specific T cell populations is determined by repetitive antigenic stimulation and environmental cytokines. J. Immunol.172(10), 6107–6114 (2004).
  • Sinclair J, Sissons P. Latency and reactivation of human cytomegalovirus. J. Gen. Virol.87(Pt 7), 1763–1779 (2006).
  • Weninger W, Manjunath N, von Andrian UH. Migration and differentiation of CD8+ T cells. Immunol. Rev.186, 221–233 (2002).
  • Holm C, Nyvold CG, Paludan SR, Thomsen AR, Hokland M. Interleukin-21 mRNA expression during virus infections. Cytokine33(1), 41–45 (2006).
  • Strengell M, Matikainen S, Siren J et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-γ production in human NK and T cells. J. Immunol.170(11), 5464–5469 (2003).
  • Lu S, Wang S, Grimes-Serrano JM. Current progress of DNA vaccine studies in humans. Expert Rev. Vaccines7(2), 175–191 (2008).
  • Dhama K, Mahendran M, Gupta PK, Rai A. DNA vaccines and their applications in veterinary practice: current perspectives. Vet. Res. Commun.32(5), 341–356 (2008).
  • Hiromatsu T, Yajima T, Matsuguchi T et al. Overexpression of interleukin-15 protects against Escherichia coli-induced shock accompanied by inhibition of tumor necrosis factor-α-induced apoptosis. J. Infect. Dis.187(9), 1442–1451 (2003).
  • Rausch A, Hessmann M, Holscher A et al. Interleukin-15 mediates protection against experimental tuberculosis: a role for NKG2D-dependent effector mechanisms of CD8+T cells. Eur. J. Immunol.36(5), 1156–1167 (2006).
  • d’Ettorre G, Andreotti M, Carnevalini M et al. Interleukin-15 enhances the secretion of IFN-γ and CC chemokines by natural killer cells from HIV viremic and aviremic patients. Immunol. Lett.103(2), 192–195 (2006).
  • Li W, Li S, Hu Y et al. Efficient augmentation of a long-lasting immune responses in HIV-1 gag DNA vaccination by IL-15 plasmid boosting. Vaccine26(26), 3282–3290 (2008).
  • Boyer JD, Robinson TM, Kutzler MA et al. Protection against simian/human immunodeficiency virus (SHIV) 89.6P in macaques after coimmunization with SHIV antigen and IL-15 plasmid. Proc. Natl Acad. Sci. USA104(47), 18648–18653 (2007).
  • Kutzler MA, Robinson TM, Chattergoon MA et al. Coimmunization with an optimized IL-15 plasmid results in enhanced function and longevity of CD8 T cells that are partially independent of CD4 T cell help. J. Immunol.175(1), 112–123 (2005).
  • Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Rα immunotherapy maximizes IL-15 activity in vivo. J. Immunol.177(9), 6072–6080 (2006).
  • Marzec M, Liu X, Kasprzycka M et al. IL-2- and IL-15-induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes. Blood111(4), 2181–2189 (2008).
  • Davis ID, Skak K, Smyth MJ et al. Interleukin-21 signaling: functions in cancer and autoimmunity. Clin. Cancer Res.13(23), 6926–6932 (2007).
  • de Totero D, Meazza R, Zupo S et al. Interleukin-21 receptor (IL-21R) is up-regulated by CD40 triggering and mediates proapoptotic signals in chronic lymphocytic leukemia B cells. Blood107(9), 3708–3715 (2006).
  • Moroz A, Eppolito C, Li Q et al. 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.173(2), 900–909 (2004).
  • Prlic M, Hernandez-Hoyos G, Bevan MJ. Duration of the initial TCR stimulus controls the magnitude but not functionality of the CD8+ T cell response. J. Exp. Med.203(9), 2135–2143 (2006).
  • Blachere NE, Morris HK, Braun D et al. IL-2 is required for the activation of memory CD8+ T cells via antigen cross-presentation. J. Immunol.176(12), 7288–7300 (2006).
  • Wan N, Dai H, Wang T et al. Bystander central memory but not effector memory CD8+ T cells suppress allograft rejection. J. Immunol.180(1), 113–121 (2008).
  • Vezys V, Masopust D, Kemball CC et al. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J. Exp. Med.203(10), 2263–2269 (2006).
  • Shin H, Blackburn SD, Blattman JN, Wherry EJ. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med.204(4), 941–949 (2007).

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