Targeting regulatory T cells to improve vaccine immunogenicity in early life

Jorjoh Ndure, Katie L Flanagan, Jorjoh Ndure, Katie L Flanagan

Abstract

Human newborns and infants are bombarded with multiple pathogens on leaving the sterile intra-uterine environment, and yet have suboptimal innate immunity and limited immunological memory, thus leading to increased susceptibility to infections in early life. They are thus the target age group for a host of vaccines against common bacterial and viral pathogens. They are also the target group for many vaccines in development, including those against tuberculosis (TB), malaria, and HIV infection. However, neonatal and infant responses too many vaccines are suboptimal, and in the case of the polysaccharide vaccines, it has been necessary to develop the alternative conjugated formulations in order to induce immunity in early life. Immunoregulatory factors are an intrinsic component of natural immunity necessary to dampen or control immune responses, with the caveat that they may also decrease immunity to infections or lead to chronic infection. This review explores the key immunoregulatory factors at play in early life, with a particular emphasis on regulatory T cells (Tregs). It goes on to explore the role that Tregs play in limiting vaccine immunogenicity, and describes animal and human studies in which Tregs have been depleted in order to enhance vaccine responses. A deeper understanding of the role that Tregs play in limiting or controlling vaccine-induced immunity would provide strategies to improve vaccine immunogenicity in this critical age group. New adjuvants and drugs are being developed that can transiently suppress Treg function, and their use as part of human vaccination strategies against infections is becoming a real prospect for the future.

Keywords: adjuvants; immune modulation; immunogenicity; infants; neonates; regulatory T cells; vaccines.

References

    1. Abbas A. K., Benoist C., Bluestone J. A., Campbell D. J., Ghosh S., Hori S., et al. (2013). Regulatory T cells: recommendations to simplify the nomenclature. Nat. Immunol. 14 307–308 10.1038/ni.2554
    1. Abel S., Luckheide N., Westendorf A. M., Geffers R., Roers A., Muller W., et al. (2012). Strong impact of CD4+ Foxp3+ regulatory T cells and limited effect of T cell-derived IL-10 on pathogen clearance during Plasmodium yoelii infection. J. Immunol. 188 5467–5477 10.4049/jimmunol.1102223
    1. Adkins B., Leclerc C., Marshall-Clarke S. (2004). Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4 553–564 10.1038/nri1394
    1. Afolabi M. O., Ndure J., Drammeh A., Darboe F., Mehedi S. R., Rowland-Jones S. L., et al. (2013). A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS ONE 8:e78289 10.1371/journal.pone.0078289
    1. Aksoy E., Albarani V., Nguyen M., Laes J. F., Ruelle J. L., De Wit D., et al. (2007). Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells. Blood 109 2887–2893 10.1182/blood-2006-06-027862
    1. Albrecht P., Ennis F. A., Saltzman E. J., Krugman S. (1977). Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure. J. Pediatr. 91 715–718 10.1016/S0022-3476(77)81021-4
    1. Andersson P. O., Olsson A., Wadenvik H. (2002). Reduced transforming growth factor-beta1 production by mononuclear cells from patients with active chronic idiopathic thrombocytopenic purpura. Br. J. Haematol. 116 862–867 10.1046/j.0007-1048.2002.03345.x
    1. Banchereau J., Pascual V., O’Garra A. (2012). From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat. Immunol. 13 925–931 10.1038/ni.2406
    1. Barbon C. M., Yang M., Wands G. D., Ramesh R., Slusher B. S., Hedley M. L., et al. (2010). Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization. Cell. Immunol. 262 150–161 10.1016/j.cellimm.2010.02.007
    1. Bayry J. (2014). Regulatory T cells as adjuvant target for enhancing the viral disease vaccine efficacy. Virusdisease 25 18–25 10.1007/s13337-013-0187-3
    1. Bejon P., Lusingu J., Olotu A., Leach A., Lievens M., Vekemans J., et al. (2008). Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359 2521–2532 10.1056/NEJMoa0807381
    1. Bejon P., Ogada E., Mwangi T., Milligan P., Lang T., Fegan G., et al. (2007). Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya. PLoS ONE 2:e707 10.1371/journal.pone.0000707
    1. Belderbos M. E., Van Bleek G. M., Levy O., Blanken M. O., Houben M. L., Schuijff L., et al. (2009). Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life. Clin. Immunol. 133 228–237 10.1016/j.clim.2009.07.003
    1. Belkaid Y. (2007). Regulatory T cells and infection: a dangerous necessity. Nat. Rev. Immunol. 7 875–888 10.1038/nri2189
    1. Belkaid Y. (2008). Paradoxical roles of Foxp3+ T cells during infection: from regulators to regulators. Cell Host Microbe 3 341–343 10.1016/j.chom.2008.05.011
    1. Belkaid Y., Piccirillo C. A., Mendez S., Shevach E. M., Sacks D. L. (2002). CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420 502–507 10.1038/nature01152
    1. Belkaid Y., Tarbell K. (2009). Regulatory T cells in the control of host-microorganism interactions (*). Annu. Rev. Immunol. 27 551–589 10.1146/annurev.immunol.021908.132723
    1. Bennett C. L., Ochs H. D. (2001). IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr. Opin. Pediatr. 13 533–538 10.1097/00008480-200112000-00007
    1. Bjorkholm B., Granstrom M., Taranger J., Wahl M., Hagberg L. (1995). Influence of high titers of maternal antibody on the serologic response of infants to diphtheria vaccination at three, five and twelve months of age. Pediatr. Infect. Dis. J. 14 846–850 10.1097/00006454-199510000-00005
    1. Burl S., Adetifa U. J., Cox M., Touray E., Ota M. O., Marchant A., et al. (2010). Delaying Bacillus Calmette-Guerin vaccination from birth to 4 1/2 months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J. Immunol. 185 2620–2628 10.4049/jimmunol.1000552
    1. Burl S., Townend J., Njie-Jobe J., Cox M., Adetifa U. J., Touray E., et al. (2011). Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants. PLoS ONE 6:e18185 10.1371/journal.pone.0018185
    1. Burstyn D. G., Baraff L. J., Peppler M. S., Leake R. D., St Geme J., Jr., Manclark C. R. (1983). Serological response to filamentous hemagglutinin and lymphocytosis-promoting toxin of Bordetella pertussis. Infect. Immun. 41 1150–1156
    1. Carr R. (2000). Neutrophil production and function in newborn infants. Br. J. Haematol. 110 18–28 10.1046/j.1365-2141.2000.01992.x
    1. Chang K. M. (2007). Regulatory T cells in hepatitis C virus infection. Hepatol. Res. 37(Suppl. 3), S327–S330 10.1111/j.1872-034X.2007.00220.x
    1. Chen Y., Kuchroo V. K., Inobe J., Hafler D. A., Weiner H. L. (1994). Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265 1237–1240 10.1126/science.7520605
    1. Ciubotariu R., Colovai A. I., Pennesi G., Liu Z., Smith D., Berlocco P., et al. (1998). Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+CD28- regulatory T cells. J. Immunol. 161 5193–5202
    1. Claesson B. A., Schneerson R., Robbins J. B., Johansson J., Lagergard T., Taranger J., et al. (1989). Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate. J. Pediatr. 114 97–100 10.1016/S0022-3476(89)80611-0
    1. Clemente A., Caporale R., Sannella A. R., Majori G., Severini C., Fadigati G., et al. (2011). Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFbeta-mediated signals. Cell. Microbiol. 13 1328–1338 10.1111/j.1462-5822.2011.01622.x
    1. Collison L. W., Workman C. J., Kuo T. T., Boyd K., Wang Y., Vignali K. M., et al. (2007). The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450 566–569 10.1038/nature06306
    1. Cusick M. F., Libbey J. E., Cox Gill J., Fujinami R. S., Eckels D. D. (2013). CD4+ T-cell engagement by both wild-type and variant HCV peptides modulates the conversion of viral clearing helper T cells to Tregs. Future Virol. 8. 10.2217/fvl.13.49
    1. Cusick M. F., Schiller J. J., Gill J. C., Eckels D. D. (2011). Hepatitis C virus induces regulatory T cells by naturally occurring viral variants to suppress T cell responses. Clin. Dev. Immunol. 2011:806061 10.1155/2011/806061
    1. Danis B., George T. C., Goriely S., Dutta B., Renneson J., Gatto L., et al. (2008). Interferon regulatory factor 7-mediated responses are defective in cord blood plasmacytoid dendritic cells. Eur. J. Immunol. 38 507–517 10.1002/eji.200737760
    1. Daum R. S., Siber G. R., Ballanco G. A., Sood S. K. (1991). Serum anticapsular antibody response in the first week after immunization of adults and infants with the Haemophilus influenzae type b-Neisseria meningitidis outer membrane protein complex conjugate vaccine. J. Infect. Dis. 164 1154–1159 10.1093/infdis/164.6.1154
    1. De La Rosa M., Rutz S., Dorninger H., Scheffold A. (2004). Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34 2480–2488 10.1002/eji.200425274
    1. De Wit D., Olislagers V., Goriely S., Vermeulen F., Wagner H., Goldman M., et al. (2004). Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns. Blood 103 1030–1032 10.1182/blood-2003-04-1216
    1. Dietze K. K., Zelinskyy G., Liu J., Kretzmer F., Schimmer S., Dittmer U. (2013). Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads. PLoS Pathog. 9:e1003798 10.1371/journal.ppat.1003798
    1. Dowling D. J., Tan Z., Prokopowicz Z. M., Palmer C. D., Matthews M. A., Dietsch G. N., et al. (2013). The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes. PLoS ONE 8:e58164 10.1371/journal.pone.0058164
    1. Duhen T., Duhen R., Lanzavecchia A., Sallusto F., Campbell D. J. (2012). Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119 4430–4440 10.1182/blood-2011-11-392324
    1. Englund J. A., Anderson E. L., Reed G. F., Decker M. D., Edwards K. M., Pichichero M. E., et al. (1995). The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics 96 580–584
    1. Fabien S., Olivier M., Khaldoun G., Vivian V., Lynda A., Laurissa O., et al. (2014). CD49b, a major marker of regulatory T-cells type 1, predicts the response to antiviral therapy of recurrent hepatitis C after liver transplantation. Biomed Res. Int. 2014:290878 10.1155/2014/290878
    1. Fan H., Yang J., Hao J., Ren Y., Chen L., Li G., et al. (2012). Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood. Immunology 136 218–230 10.1111/j.1365-2567.2012.03573.x
    1. Filaci G., Fravega M., Negrini S., Procopio F., Fenoglio D., Rizzi M., et al. (2004). Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum. Immunol. 65 142–156 10.1016/j.humimm.2003.12.001
    1. Flanagan K. L., Halliday A., Burl S., Landgraf K., Jagne Y. J., Noho-Konteh F., et al. (2010). The effect of placental malaria infection on cord blood and maternal immunoregulatory responses at birth. Eur. J. Immunol. 40 1062–1072 10.1002/eji.200939638
    1. Fontenot J. D., Gavin M. A., Rudensky A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4 330–336 10.1038/ni904
    1. Fujimaki W., Takahashi N., Ohnuma K., Nagatsu M., Kurosawa H., Yoshida S., et al. (2008). Comparative study of regulatory T cell function of human CD25CD4 T cells from thymocytes, cord blood, and adult peripheral blood. Clin. Dev. Immunol. 2008:305859 10.1155/2008/305859
    1. Gaardbo J. C., Hartling H. J., Ronit A., Springborg K., Gjerdrum L. M., Ralfkiaer E., et al. (2014). Regulatory T cells in HIV-infected immunological non-responders are increased in blood but depleted in lymphoid tissue and predict immunological reconstitution. J. Acquir. Immune Defic. Syndr. 66 349–357 10.1097/QAI.0000000000000173
    1. Gagliani N., Magnani C. F., Huber S., Gianolini M. E., Pala M., Licona-Limon P., et al. (2013). Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19 739–746 10.1038/nm.3179
    1. Gambineri E., Torgerson T. R., Ochs H. D. (2003). Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr. Opin. Rheumatol. 15 430–435 10.1097/00002281-200307000-00010
    1. Gans H. A., Arvin A. M., Galinus J., Logan L., Dehovitz R., Maldonado Y. (1998). Deficiency of the humoral immune response to measles vaccine in infants immunized at age 6 months. JAMA 280 527–532 10.1001/jama.280.6.527
    1. Ghazal P., Dickinson P., Smith C. L. (2013). Early life response to infection. Curr. Opin. Infect. Dis. 26 213–218 10.1097/QCO.0b013e32835fb8bf
    1. Godfrey W. R., Spoden D. J., Ge Y. G., Baker S. R., Liu B., Levine B. L., et al. (2005). Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 105 750–758 10.1182/blood-2004-06-2467
    1. Goebel J., Stevens E., Forrest K., Roszman T. L. (2000). Daclizumab (Zenapax) inhibits early interleukin-2 receptor signal transduction events. Transpl. Immunol. 8 153–159 10.1016/S0966-3274(00)00021-6
    1. Goriely S., Van Lint C., Dadkhah R., Libin M., De Wit D., Demonte D., et al. (2004). A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J. Exp. Med. 199 1011–1016 10.1084/jem.20031272
    1. Gregori S., Goudy K. S., Roncarolo M. G. (2012). The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells. Front. Immunol. 3:30 10.3389/fimmu.2012.00030
    1. Gregori S., Tomasoni D., Pacciani V., Scirpoli M., Battaglia M., Magnani C. F., et al. (2010). Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 116 935–944 10.1182/blood-2009-07-234872
    1. Griffioen A. W., Franklin S. W., Zegers B. J., Rijkers G. T. (1993). Expression and functional characteristics of the complement receptor type 2 on adult and neonatal B lymphocytes. Clin. Immunol. Immunopathol. 69 1–8 10.1006/clin.1993.1142
    1. Groux H., O’Garra A., Bigler M., Rouleau M., Antonenko S., De Vries J. E., et al. (1997). A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389 737–742 10.1038/39614
    1. Guilmot A., Hermann E., Braud V. M., Carlier Y., Truyens C. (2011). Natural killer cell responses to infections in early life. J. Innate Immun. 3 280–288 10.1159/000323934
    1. Halliday J., Klenerman P., Barnes E. (2011). Vaccination for hepatitis C virus: closing in on an evasive target. Expert Rev. Vaccines 10 659–672 10.1586/erv.11.55
    1. Hatakeyama M., Tsudo M., Minamoto S., Kono T., Doi T., Miyata T., et al. (1989). Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA’s. Science 244 551–556 10.1126/science.2785715
    1. Higashitani K., Kanto T., Kuroda S., Yoshio S., Matsubara T., Kakita N., et al. (2013). Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection. J. Gastroenterol. 48 660–670 10.1007/s00535-012-0667-z
    1. Ho P., Wei X., Seah G. T. (2010). Regulatory T cells induced by Mycobacterium chelonae sensitization influence murine responses to bacille Calmette-Guerin. J. Leukoc. Biol. 88 1073–1080 10.1189/jlb.0809582
    1. Horenstein A. L., Chillemi A., Zaccarello G., Bruzzone S., Quarona V., Zito A., et al. (2013). A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology 2:e26246 10.4161/onci.26246
    1. Hori S., Nomura T., Sakaguchi S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science 299 1057–1061 10.1126/science.1079490
    1. Hu D., Ikizawa K., Lu L., Sanchirico M. E., Shinohara M. L., Cantor H. (2004). Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat. Immunol. 5 516–523 10.1038/ni1063
    1. Jepsen M. P., Jogdand P. S., Singh S. K., Esen M., Christiansen M., Issifou S., et al. (2013). The malaria vaccine candidate GMZ2 elicits functional antibodies in individuals from malaria endemic and non-endemic areas. J. Infect. Dis. 208 479–488 10.1093/infdis/jit185
    1. Jones C., Pollock L., Barnett S. M., Battersby A., Kampmann B. (2014). The relationship between concentration of specific antibody at birth and subsequent response to primary immunization. Vaccine 32 996–1002 10.1016/j.vaccine.2013.11.104
    1. Kaleebu P., Njai H. F., Wang L., Jones N., Ssewanyana I., Richardson P., et al. (2014). Immunogenicity of ALVAC-HIV vCP1521 in infants of HIV-1-infected women in Uganda (HPTN 027): the first pediatric HIV vaccine trial in Africa. J. Acquir. Immune Defic. Syndr. 65 268–277 10.1097/01.qai.0000435600.65845.31
    1. Kanegane H., Miyawaki T., Kato K., Yokoi T., Uehara T., Yachie A., et al. (1991). A novel subpopulation of CD45RA+ CD4+ T cells expressing IL-2 receptor alpha-chain (CD25) and having a functionally transitional nature into memory cells. Int. Immunol. 3 1349–1356 10.1093/intimm/3.12.1349
    1. Kanra G., Yalcin S. S., Ceyhan M., Yurdakok K. (2000). Clinical trial to evaluate immunogenicity and safety of inactivated hepatitis A vaccination starting at 2-month-old children. Turk. J. Pediatr. 42 105–108
    1. Kao J. Y., Zhang M., Miller M. J., Mills J. C., Wang B., Liu M., et al. (2010). Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice. Gastroenterology 138 1046–1054 10.1053/j.gastro.2009.11.043
    1. Kared H., Fabre T., Bedard N., Bruneau J., Shoukry N. H. (2013). Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathog. 9:e1003422 10.1371/journal.ppat.1003422
    1. Keenan B. P., Saenger Y., Kafrouni M. I., Leubner A., Lauer P., Maitra A., et al. (2014). A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 146 1784e6–1794e6. 10.1053/j.gastro.2014.02.055
    1. Klages K., Mayer C. T., Lahl K., Loddenkemper C., Teng M. W., Ngiow S. F., et al. (2010). Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res. 70 7788–7799 10.1158/0008-5472.CAN-10-1736
    1. Kohm A. P., Mcmahon J. S., Podojil J. R., Begolka W. S., Degutes M., Kasprowicz D. J., et al. (2006). Cutting Edge: Anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells. J. Immunol. 176 3301–3305 10.4049/jimmunol.176.6.3301
    1. Kollmann T. R., Crabtree J., Rein-Weston A., Blimkie D., Thommai F., Wang X. Y., et al. (2009). Neonatal innate TLR-mediated responses are distinct from those of adults. J. Immunol. 183 7150–7160 10.4049/jimmunol.0901481
    1. Kollmann T. R., Levy O., Montgomery R. R., Goriely S. (2012). Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37 771–783 10.1016/j.immuni.2012.10.014
    1. Koukouikila-Koussounda F., Ntoumi F., Ndounga M., Tong H. V., Abena A. A., Velavan T. P. (2013). Genetic evidence of regulatory gene variants of the STAT6, IL10R and FOXP3 locus as a susceptibility factor in uncomplicated malaria and parasitaemia in Congolese children. Malar. J. 12:9 10.1186/1475-2875-12-9
    1. Kruetzmann S., Rosado M. M., Weber H., Germing U., Tournilhac O., Peter H. H., et al. (2003). Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J. Exp. Med. 197 939–945 10.1084/jem.20022020
    1. Lacan G., Dang H., Middleton B., Horwitz M. A., Tian J., Melega W. P., et al. (2013). Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J. Neurosci. Res. 91 1292–1302 10.1002/jnr.23253
    1. Lahl K., Sparwasser T. (2011). In vivo depletion of FoxP3+ Tregs using the DEREG mouse model. Methods Mol. Biol. 707 157–172 10.1007/978-1-61737-979-6_10
    1. Langrish C. L., Buddle J. C., Thrasher A. J., Goldblatt D. (2002). Neonatal dendritic cells are intrinsically biased against Th-1 immune responses. Clin. Exp. Immunol. 128 118–123 10.1046/j.1365-2249.2002.01817.x
    1. Laurens M. B., Thera M. A., Coulibaly D., Ouattara A., Kone A. K., Guindo A. B., et al. (2013). Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in Malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial. PLoS ONE 8:e79323 10.1371/journal.pone.0079323
    1. Le D. T., Jaffee E. M. (2012). Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res. 72 3439–3444 10.1158/0008-5472.CAN-11-3912
    1. Levings M. K., Roncarolo M. G. (2000). T-regulatory 1 cells: a novel subset of CD4 T cells with immunoregulatory properties. J. Allergy Clin. Immunol. 106 S109–S112 10.1067/mai.2000.106635
    1. Levy O. (2007). Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7 379–390 10.1038/nri2075
    1. Levy O., Coughlin M., Cronstein B. N., Roy R. M., Desai A., Wessels M. R. (2006). The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J. Immunol. 177 1956–1966 10.4049/jimmunol.177.3.1956
    1. Levy O., Wynn J. L. (2014). A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology 105 136–141 10.1159/000356035
    1. Lin S. J., Lu C. H., Yan D. C., Lee P. T., Hsiao H. S., Kuo M. L. (2014). Expansion of regulatory T cells from umbilical cord blood and adult peripheral blood CD4CD25 T cells. Immunol. Res. 10.1007/s12026-014-8488-1 [Epub ahead of print]
    1. Liu W., Putnam A. L., Xu-Yu Z., Szot G. L., Lee M. R., Zhu S., et al. (2006). CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203 1701–1711 10.1084/jem.20060772
    1. Liu Y., Lan Q., Lu L., Chen M., Xia Z., Ma J., et al. (2014). Phenotypic and functional characteristic of a newly identified CD8+ Foxp3- CD103+ regulatory T cells. J. Mol. Cell Biol. 6 81–92 10.1093/jmcb/mjt026
    1. Lu L., Kim H. J., Werneck M. B., Cantor H. (2008). Regulation of CD8+ regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc. Natl. Acad. Sci. U.S.A. 105 19420–19425 10.1073/pnas.0810383105
    1. Lu W., Chen S., Lai C., Guo W., Fu L., Andrieu J. M. (2012). Induction of CD8+ regulatory T cells protects macaques against SIV challenge. Cell Rep. 2 1736–1746 10.1016/j.celrep.2012.11.016
    1. Luciano A. A., Arbona-Ramirez I. M., Ruiz R., Llorens-Bonilla B. J., Martinez-Lopez D. G., Funderburg N., et al. (2014). Alterations in regulatory T cell subpopulations seen in preterm infants. PLoS ONE 9:e95867 10.1371/journal.pone.0095867
    1. Ly N. P., Ruiz-Perez B., Mcloughlin R. M., Visness C. M., Wallace P. K., Cruikshank W. W., et al. (2009). Characterization of regulatory T cells in urban newborns. Clin. Mol. Allergy 7:8 10.1186/1476-7961-7-8
    1. Macatangay B. J., Szajnik M. E., Whiteside T. L., Riddler S. A., Rinaldo C. R. (2010). Regulatory T cell suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PLoS ONE 5:e9852 10.1371/journal.pone.0009852
    1. Macdonald A. J., Duffy M., Brady M. T., Mckiernan S., Hall W., Hegarty J., et al. (2002). CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J. Infect. Dis. 185 720–727 10.1086/339340
    1. Mandapathil M., Hilldorfer B., Szczepanski M. J., Czystowska M., Szajnik M., Ren J., et al. (2010). Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J. Biol. Chem. 285 7176–7186 10.1074/jbc.M109.047423
    1. Marchant A., Goetghebuer T., Ota M. O., Wolfe I., Ceesay S. J., De Groote D., et al. (1999). Newborns develop a Th1-type immune response to Mycobacterium bovis Bacillus Calmette-Guerin vaccination. J. Immunol. 163 2249–2255
    1. Mattarollo S. R., Steegh K., Li M., Duret H., Foong Ngiow S., Smyth M. J. (2013). Transient Foxp3(+) regulatory T-cell depletion enhances therapeutic anticancer vaccination targeting the immune-stimulatory properties of NKT cells. Immunol. Cell Biol. 91 105–114 10.1038/icb.2012.58
    1. Mayer C. T., Floess S., Baru A. M., Lahl K., Huehn J., Sparwasser T. (2011). CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity. Eur. J. Immunol. 41 716–725 10.1002/eji.201040913
    1. Mayer E., Bannert C., Gruber S., Klunker S., Spittler A., Akdis C. A., et al. (2012). Cord blood derived CD4+ CD25(high) T cells become functional regulatory T cells upon antigen encounter. PLoS ONE 7:e29355 10.1371/journal.pone.0029355
    1. Mills K. H., Mcguirk P. (2004). Antigen-specific regulatory T cells – their induction and role in infection. Semin. Immunol. 16 107–117 10.1016/j.smim.2003.12.006
    1. Minigo G., Woodberry T., Piera K. A., Salwati E., Tjitra E., Kenangalem E., et al. (2009). Parasite-dependent expansion of TNF receptor II-positive regulatory T cells with enhanced suppressive activity in adults with severe malaria. PLoS Pathog. 5:e1000402 10.1371/journal.ppat.1000402
    1. Mitchell D. A., Cui X., Schmittling R. J., Sanchez-Perez L., Snyder D. J., Congdon K. L., et al. (2011). Monoclonal antibody blockade of IL-2 receptor alpha during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood 118 3003–3012 10.1182/blood-2011-02-334565
    1. Miyara M., Yoshioka Y., Kitoh A., Shima T., Wing K., Niwa A., et al. (2009). Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30 899–911 10.1016/j.immuni.2009.03.019
    1. Moore A. C., Gallimore A., Draper S. J., Watkins K. R., Gilbert S. C., Hill A. V. (2005). Anti-CD25 antibody enhancement of vaccine-induced immunogenicity: increased durable cellular immunity with reduced immunodominance. J. Immunol. 175 7264–7273 10.4049/jimmunol.175.11.7264
    1. Moorman J. P., Wang J. M., Zhang Y., Ji X. J., Ma C. J., Wu X. Y., et al. (2012). Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection. J. Immunol. 189 755–766 10.4049/jimmunol.1200162
    1. Mwacharo J., Dunachie S. J., Kai O., Hill A. V., Bejon P., Fletcher H. A. (2009). Quantitative PCR evaluation of cellular immune responses in Kenyan children vaccinated with a candidate malaria vaccine. PLoS ONE 4:e8434 10.1371/journal.pone.0008434
    1. Nettenstrom L., Alderson K., Raschke E. E., Evans M. D., Sondel P. M., Olek S., et al. (2013). An optimized multi-parameter flow cytometry protocol for human T regulatory cell analysis on fresh and viably frozen cells, correlation with epigenetic analysis, and comparison of cord and adult blood. J. Immunol. Methods 387 81–88 10.1016/j.jim.2012.09.014
    1. Ngamphaiboon J., Theamboonlert A., Poovorawan Y. (1998). Serum IgG subclass levels in a group of healthy Thai children. Asian Pac. J. Allergy Immunol. 16 49–55
    1. Nguyen M., Leuridan E., Zhang T., De Wit D., Willems F., Van Damme P., et al. (2010). Acquisition of adult-like TLR4 and TLR9 responses during the first year of life. PLoS ONE 5:e10407 10.1371/journal.pone.0010407
    1. Ogwang C., Afolabi M., Kimani D., Jagne Y. J., Sheehy S. H., Bliss C. M., et al. (2013). Safety and immunogenicity of heterologous prime-boost immunisation with Plasmodium falciparum malaria candidate vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in healthy Gambian and Kenyan adults. PLoS ONE 8:e57726 10.1371/journal.pone.0057726
    1. Olotu A., Fegan G., Wambua J., Nyangweso G., Awuondo K. O., Leach A., et al. (2013). Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N. Engl. J. Med. 368 1111–1120 10.1056/NEJMoa1207564
    1. Olotu A., Lusingu J., Leach A., Lievens M., Vekemans J., Msham S., et al. (2011). Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect. Dis. 11 102–109 10.1016/S1473-3099(10)70262-0
    1. Patton D. T., Wilson M. D., Rowan W. C., Soond D. R., Okkenhaug K. (2011). The PI3K p110delta regulates expression of CD38 on regulatory T cells. PLoS ONE 6:e17359 10.1371/journal.pone.0017359
    1. Peggs K. S., Quezada S. A., Chambers C. A., Korman A. J., Allison J. P. (2009). Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206 1717–1725 10.1084/jem.20082492
    1. Perez-Machado M. A., Ashwood P., Thomson M. A., Latcham F., Sim R., Walker-Smith J. A., et al. (2003). Reduced transforming growth factor-beta1-producing T cells in the duodenal mucosa of children with food allergy. Eur. J. Immunol. 33 2307–2315 10.1002/eji.200323308
    1. Perret R., Sierro S. R., Botelho N. K., Corgnac S., Donda A., Romero P. (2013). Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity. Cancer Res. 73 6597–6608 10.1158/0008-5472.CAN-13-0875
    1. Philbin V. J., Dowling D. J., Gallington L. C., Cortes G., Tan Z., Suter E. E., et al. (2012). Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways. J. Allergy Clin. Immunol. 130 195e9–204e9. 10.1016/j.jaci.2012.02.042
    1. Philbin V. J., Levy O. (2009). Developmental biology of the innate immune response: implications for neonatal and infant vaccine development. Pediatr. Res. 65 98R–105R 10.1203/PDR.0b013e31819f195d
    1. Power Coombs M. R., Belderbos M. E., Gallington L. C., Bont L., Levy O. (2011). Adenosine modulates Toll-like receptor function: basic mechanisms and translational opportunities. Expert Rev. Anti Infect. Ther. 9 261–269 10.1586/eri.10.158
    1. Raskovalova T., Huang X., Sitkovsky M., Zacharia L. C., Jackson E. K., Gorelik E. (2005). Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J. Immunol. 175 4383–4391 10.4049/jimmunol.175.7.4383
    1. Rech A. J., Mick R., Martin S., Recio A., Aqui N. A., Powell D. J., et al. (2012). CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 4:134ra62
    1. Rech A. J., Vonderheide R. H. (2009). Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann. N. Y. Acad. Sci. 1174 99–106 10.1111/j.1749-6632.2009.04939.x
    1. Roncarolo M. G., Gregori S., Battaglia M., Bacchetta R., Fleischhauer K., Levings M. K. (2006). Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212 28–50 10.1111/j.0105-2896.2006.00420.x
    1. Rts S. C. T. P., Agnandji S. T., Lell B., Fernandes J. F., Abossolo B. P., Methogo B. G., et al. (2012). A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367 2284–2295 10.1056/NEJMoa1208394
    1. Saison J., Ferry T., Demaret J., Maucort Boulch D., Venet F., Perpoint T., et al. (2014). Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients. Clin. Exp. Immunol. 176 401–409 10.1111/cei.12278
    1. Sakaguchi S. (2000). Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101 455–458 10.1016/S0092-8674(00)80856-9
    1. Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M. (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155 1151–1164
    1. Sallusto F., Lenig D., Forster R., Lipp M., Lanzavecchia A. (1999). Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401 708–712 10.1038/44385
    1. Sansom D. M., Walker L. S. (2006). The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol. Rev. 212 131–148 10.1111/j.0105-2896.2006.00419.x
    1. Santner-Nanan B., Seddiki N., Zhu E., Quent V., Kelleher A., Fazekas De St Groth B., et al. (2008). Accelerated age-dependent transition of human regulatory T cells to effector memory phenotype. Int. Immunol. 20 375–383 10.1093/intimm/dxm151
    1. Scalzo-Inguanti K., Plebanski M. (2011). CD38 identifies a hypo-proliferative IL-13-secreting CD4+ T-cell subset that does not fit into existing naive and memory phenotype paradigms. Eur. J. Immunol. 41 1298–1308 10.1002/eji.201040726
    1. Schmetterer K. G., Neunkirchner A., Pickl W. F. (2012). Naturally occurring regulatory T cells: markers, mechanisms, and manipulation. FASEB J. 26 2253–2276 10.1096/fj.11-193672
    1. Scholzen A., Minigo G., Plebanski M. (2010). Heroes or villains? T regulatory cells in malaria infection. Trends Parasitol. 26 16–25 10.1016/j.pt.2009.10.004
    1. Scholzen A., Mittag D., Rogerson S. J., Cooke B. M., Plebanski M. (2009). Plasmodium falciparum-mediated induction of human CD25Foxp3 CD4 T cells is independent of direct TCR stimulation and requires IL-2 IL-10 and TGFbeta. PLoS Pathog. 5:e1000543 10.1371/journal.ppat.1000543
    1. Seddiki N., Santner-Nanan B., Martinson J., Zaunders J., Sasson S., Landay A., et al. (2006). Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203 1693–1700 10.1084/jem.20060468
    1. Serana F., Chiarini M., Quiros-Roldan E., Gotti D., Zanotti C., Sottini A., et al. (2014). Modulation of regulatory T-cell subsets in very long-term treated aviremic HIV(+) patients and untreated viremic patients. Open AIDS J. 8 1–6 10.2174/1874613601408010001
    1. Siegrist C. A. (2003). Mechanisms by which maternal antibodies influence infant vaccine responses: review of hypotheses and definition of main determinants. Vaccine 21 3406–3412 10.1016/S0264-410X(03)00342-6
    1. Siegrist C. A., Barrios C., Martinez X., Brandt C., Berney M., Cordova M., et al. (1998). Influence of maternal antibodies on vaccine responses: inhibition of antibody but not T cell responses allows successful early prime-boost strategies in mice. Eur. J. Immunol. 28 4138–4148 10.1002/(SICI)1521-4141(199812)28:12<4138::AID-IMMU4138>;2-L
    1. Simone R., Zicca A., Saverino D. (2008). The frequency of regulatory CD3+CD8+CD28- CD25+ T lymphocytes in human peripheral blood increases with age. J. Leukoc. Biol. 84 1454–1461 10.1189/jlb.0907627
    1. Sitkovsky M. V., Ohta A. (2005). The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol. 26 299–304 10.1016/j.it.2005.04.004
    1. Smith T. R., Kumar V. (2008). Revival of CD8+ Treg-mediated suppression. Trends Immunol. 29 337–342 10.1016/j.it.2008.04.002
    1. Suzuki M., Jagger A. L., Konya C., Shimojima Y., Pryshchep S., Goronzy J. J., et al. (2012). CD8+CD45RA+CCR7+FOXP3+ T cells with immunosuppressive properties: a novel subset of inducible human regulatory T cells. J. Immunol. 189 2118–2130 10.4049/jimmunol.1200122
    1. Suzuki M., Konya C., Goronzy J. J., Weyand C. M. (2008). Inhibitory CD8+ T cells in autoimmune disease. Hum. Immunol. 69 781–789 10.1016/j.humimm.2008.08.283
    1. Takahata Y., Nomura A., Takada H., Ohga S., Furuno K., Hikino S., et al. (2004). CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp. Hematol. 32 622–629 10.1016/j.exphem.2004.03.012
    1. Tan C., Reddy V., Dannull J., Ding E., Nair S. K., Tyler D. S., et al. (2013). Impact of anti-CD25 monoclonal antibody on dendritic cell-tumor fusion vaccine efficacy in a murine melanoma model. J. Transl. Med. 11:148 10.1186/1479-5876-11-148
    1. Todryk S. M., Bejon P., Mwangi T., Plebanski M., Urban B., Marsh K., et al. (2008). Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans. PLoS ONE 3:e2027 10.1371/journal.pone.0002027
    1. Tosello V., Odunsi K., Souleimanian N. E., Lele S., Shrikant P., Old L. J., et al. (2008). Differential expression of CCR7 defines two distinct subsets of human memory CD4+CD25+ Tregs. Clin. Immunol. 126 291–302 10.1016/j.clim.2007.11.008
    1. Uss E., Rowshani A. T., Hooibrink B., Lardy N. M., Van Lier R. A., Ten Berge I. J. (2006). CD103 is a marker for alloantigen-induced regulatory CD8+ T cells. J. Immunol. 177 2775–2783 10.4049/jimmunol.177.5.2775
    1. Vieira P. L., Christensen J. R., Minaee S., O’Neill E. J., Barrat F. J., Boonstra A., et al. (2004). IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol. 172 5986–5993 10.4049/jimmunol.172.10.5986
    1. Voo K. S., Bover L., Harline M. L., Vien L. T., Facchinetti V., Arima K., et al. (2013). Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J. Immunol. 191 3641–3650 10.4049/jimmunol.1202752
    1. Walker L. S. (2013). Treg and CTLA-4: two intertwining pathways to immune tolerance. J. Autoimmun. 45 49–57 10.1016/j.jaut.2013.06.006
    1. Walther B., Miles D. J., Waight P., Palmero M. S., Ojuola O., Touray E. S., et al. (2012). Placental malaria is associated with attenuated CD4 T-cell responses to tuberculin PPD 12 months after BCG vaccination. BMC Infect. Dis. 12:6 10.1186/1471-2334-12-6
    1. Walther M., Jeffries D., Finney O. C., Njie M., Ebonyi A., Deininger S., et al. (2009). Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 5:e1000364 10.1371/journal.ppat.1000364
    1. Walther M., Tongren J. E., Andrews L., Korbel D., King E., Fletcher H., et al. (2005). Upregulation of TGF-beta, FOXP3 and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23 287–296 10.1016/j.immuni.2005.08.006
    1. Wammes L. J., Wiria A. E., Toenhake C. G., Hamid F., Liu K. Y., Suryani H., et al. (2013). Asymptomatic plasmodial infection is associated with increased tumor necrosis factor receptor II-expressing regulatory T cells and suppressed type 2 immune responses. J. Infect. Dis. 207 1590–1599 10.1093/infdis/jit058
    1. Wang W. H., Ming L., Wang Y., Kan Q. C., Zhang X. Y. (2013). High frequency of regulatory T cells among HIV type 1-infected men who have sex with men correlates with disease progression. Chin. Med. J. (Engl.) 126 2054–2061
    1. Wing J. B., Sakaguchi S. (2012). Multiple Treg suppressive modules and their adaptability. Front. Immunol. 3:178 10.3389/fimmu.2012.00178
    1. Wing K., Ekmark A., Karlsson H., Rudin A., Suri-Payer E. (2002). Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 106 190–199 10.1046/j.1365-2567.2002.01412.x
    1. Wing K., Larsson P., Sandstrom K., Lundin S. B., Suri-Payer E., Rudin A. (2005). CD4+ CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology 115 516–525 10.1111/j.1365-2567.2005.02186.x
    1. Wing K., Yamaguchi T., Sakaguchi S. (2011). Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends Immunol. 32 428–433 10.1016/j.it.2011.06.002
    1. Wu J. J., Chen G., Liu J., Wang T., Zheng W., Cao Y. M. (2010). Natural regulatory T cells mediate the development of cerebral malaria by modifying the pro-inflammatory response. Parasitol. Int. 59 232–241 10.1016/j.parint.2010.02.007
    1. Yeung L. T., King S. M., Roberts E. A. (2001). Mother-to-infant transmission of hepatitis C virus. Hepatology 34 223–229 10.1053/jhep.2001.25885
    1. Zandvoort A., Timens W. (2002). The dual function of the splenic marginal zone: essential for initiation of anti-TI-2 responses but also vital in the general first-line defense against blood-borne antigens. Clin. Exp. Immunol. 130 4–11 10.1046/j.1365-2249.2002.01953.x

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi