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Journal of Laboratory Medicine

Official Journal of the German Society of Clinical Chemistry and Laboratory Medicine

Editor-in-Chief: Schuff-Werner, Peter

Ed. by Ahmad-Nejad, Parviz / Bidlingmaier, Martin / Bietenbeck, Andreas / Conrad, Karsten / Findeisen, Peter / Fraunberger, Peter / Ghebremedhin, Beniam / Holdenrieder, Stefan / Kiehntopf, Michael / Klein, Hanns-Georg / Kohse, Klaus P. / Kratzsch, Jürgen / Luppa, Peter B. / Meyer, Alexander von / Nebe, Carl Thomas / Orth, Matthias / Röhrig-Herzog, Gabriele / Sack, Ulrich / Steimer, Werner / Weber, Thomas / Wieland, Eberhard / Winter, Christof / Zettl, Uwe K.


IMPACT FACTOR 2018: 0.389

CiteScore 2018: 0.22

SCImago Journal Rank (SJR) 2018: 0.156
Source Normalized Impact per Paper (SNIP) 2018: 0.089

Online
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2567-9449
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Volume 37, Issue 3

Issues

Das neonatale Immunsystem: Modulation durch regulatorische T-Zellen und CTLA-4 (CD152)

The neonatal immune system: modulation by regulatory T-cells and CTLA-4

Katrin Hebel / Mandy Pierau / Holger Lingel / Michael Steiner / Hardy Krause / Gerhard Jorch / Monika C. Brunner-Weinzierl
Published Online: 2013-05-07 | DOI: https://doi.org/10.1515/labmed-2012-0061

Zusammenfassung

Fehlregulationen von CTLA-4 (CD152), einem auf der Oberfläche von Lymphozyten exprimiertem Glykoprotein, können zu chronischen Entzündungsreaktionen führen. Aufgrund neuer Erkenntnisse wird deutlich, dass CTLA-4 die Effektorfunktionen von T-Lymphozyten abschaltet und damit die Effektorphase von T-Lymphozyten beendet. Interessanterweise sind die CTLA-4 exprimierenden T-Lymphozyten resistent gegen Apoptose (programmierter Zelltod) und migrieren verstärkt in Lymphknoten und Gewebe. Weitere Studien zeigen, dass regulatorische T-Zellen, die unerwünschte Immunantworten abschalten, in vivo nur inhibieren können, wenn Sie über ein intaktes CTLA-4-Gen verfügen. Darüber hinaus hat sich bestätigt, dass CTLA-4 nicht nur-wie angenommen-auf T-Lymphozyten exprimiert wird, sondern auch auf B-Lymphozyten. So zeigen Mäuse mit genetischer Inaktivierung von CTLA-4 in B-Lymphozyten eine verstärkte Produktion von IgM nach Immunisierung. Interessanterweise exprimieren insbesondere B-Lymphozyten und T-Lymphozyten von Neugeborenen und Kleinkindern stark CTLA-4, was auf eine zentrale immunregulatorische Rolle bei frühkindlichen Immunantworten hindeutet. Moleküle, die wie CTLA-4 die Differenzierung von Lymphozyten regulieren, könnten einen neuen Ansatzpunkt bieten, um bereits im Kindesalter die Weichen für ein vor Autoimmunität und Allergie geschütztes Immunsystem zu stellen.

Abstract

The dysregulation of CTLA-4 (CD152), a glycoprotein expressed on the surface of lymphocytes, may lead to chronic inflammation. Based on the recent scientific findings, it has become clear that CTLA-4 inhibits the effector function and, thus, shuts down the effector phase of the T-lymphocytes. Interestingly, the CTLA-4-expressing cells become resistant to apoptosis (programmed cell death) and increasingly migrate to the lymph nodes and tissues. Studies have shown that regulatory T cells (Tregs), which switch off unwanted immune responses can inhibit in vivo only if they express an intact CTLA-4 gene. Moreover, it was confirmed that CTLA-4 is not only expressed on the T-lymphocytes but also on the B-lymphocytes. The mice with genetic inactivation of CTLA-4 in the B-lymphocytes show an increased production of the IgM antibodies after immunization. Interestingly, in particular, the B- and T-lymphocytes from the newborns and infants show a strongly increased CTLA-4 expression, suggesting a key immunoregulatory role in the neonatal immune responses. The molecules such as CTLA-4, which regulate the differentiation of the lymphocytes, could provide therapeutic targets during the early childhood to set the course for protection against autoimmunity and allergy.

Reviewed publication

ConradU. Sack/K.

Keywords: Effektorzellen; Immunsystem; Kinder; Lymphozyten; Neugeborene; Regulatorische T-Zellen; Antikörper; antibody; effector T-cell; immune system; infants; lymphocytes; newborns; regulatory T-cell

Literatur

  • 1.

    Brunner-Weinzierl MC, Hoff H, Burmester GR. Multiple functions for CD28 and cytotoxic T lymphocyte antigen-4 during different phases of T cell responses: implications for arthritis and autoimmune diseases. Arthritis Res Ther 2004;6:45–54.Google Scholar

  • 2.

    Chambers CA, Sullivan TJ, Allison JP. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 1997;7:885–95.PubMedCrossrefGoogle Scholar

  • 3.

    Chambers CA, Kuhns MS, Allison JP. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci USA 1999;96:8603–8.CrossrefGoogle Scholar

  • 4.

    Maszyna F, Hoff H, Kunkel D, Radbruch A, Brunner-Weinzierl MC. Diversity of clonal T cell proliferation is mediated by differential expression of CD152 (CTLA-4) on the cell surface of activated individual T lymphocytes. J Immunol 2003;171: 3459–66.Google Scholar

  • 5.

    Waterhouse P, Marengere LE, Mittrucker HW, Mak TW. CTLA-4, a negative regulator of T-lymphocyte activation. Immunol Rev 1996;153:183–7.Google Scholar

  • 6.

    Kormendy D, Hoff H, Hoff P, Broker BM, Burmester GR, Brunner-Weinzierl MC. Impact of the CTLA-4/CD28 axis on the processes of joint inflammation in rheumatoid arthritis. Arthritis Rheum 2013;65:81–7.Google Scholar

  • 7.

    Hoff H, Knieke K, Cabail Z, Hirseland H, Vratsanos G, Burmester GR, et al. Surface CD152 (CTLA-4) expression and signaling dictates longevity of CD28null T cells. J Immunol 2009;182:5342–51.Google Scholar

  • 8.

    Baroja ML, Vijayakrishnan L, Bettelli E, Darlington PJ, Chau TA, Ling V, et al. Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. J Immunol 2002;168:5070–8.Google Scholar

  • 9.

    Marengere LE, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 1996;272:1170–3.Google Scholar

  • 10.

    Pandiyan P, Gartner D, Soezeri O, Radbruch A, Schulze-Osthoff K, Brunner-Weinzierl MC. CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. J Exp Med 2004;199:831–42.Google Scholar

  • 11.

    Knieke K, Lingel H, Chamaon K, Brunner-Weinzierl MC. Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4)-mediated signaling via PI3 kinase-dependent Akt activation. PLoS One 2012;7:e31391.Google Scholar

  • 12.

    Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002;16:23–35.Google Scholar

  • 13.

    Hoff H, Burmester GR, Brunner-Weinzierl MC. CD28 and CD152: competition and cooperation. Signal Transduction 2006;4:260–7.Google Scholar

  • 14.

    Pentcheva-Hoang T, Egen JG, Wojnoonski K, Allison JP. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 2004;21:401–13.Google Scholar

  • 15.

    Allison JP, Chambers C, Hurwitz, Sullivan T, Boitel B, Fournier SA, et al. A role for CTLA-4-mediated inhibitory signals in peripheral T cell tolerance? Novartis Found Symp 1998;215:92–8.Google Scholar

  • 16.

    Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 1996;4:535–43.PubMedCrossrefGoogle Scholar

  • 17.

    Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002;3:611–8.CrossrefPubMedGoogle Scholar

  • 18.

    Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol 1999;162:5813–20.Google Scholar

  • 19.

    Frauwirth KA, Thompson CB. Activation and inhibition of lymphocytes by costimulation. J Clin Invest 2002;109: 295–9.Google Scholar

  • 20.

    Pandiyan P, Hegel JK, Krueger M, Quandt D, Brunner-Weinzierl MC. High IFN-gamma production of individual CD8 T lymphocytes is controlled by CD152 (CTLA-4). J Immunol 2007;178:2132–40.Web of ScienceGoogle Scholar

  • 21.

    Hegel JK, Knieke K, Kolar P, Reiner SL, Brunner-Weinzierl MC. CD152 (CTLA-4) regulates effector functions of CD8+ T lymphocytes by repressing Eomesodermin. Eur J Immunol 2009;39:883–93.Web of ScienceGoogle Scholar

  • 22.

    Seder RA, Darrah PA, Roederer M. T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 2008;8:247–58.CrossrefWeb of SciencePubMedGoogle Scholar

  • 23.

    Knieke K, Hoff H, Maszyna F, Kolar P, Schrage A, Hamann A, et al. CD152 (CTLA-4) determines CD4 T cell migration in vitro and in vivo. PLoS One 2009;4:e5702.Google Scholar

  • 24.

    Riley JL, Schlienger K, Blair PJ, Carreno B, Craighead N, Kim D, et al. Modulation of susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule. J Exp Med 2000;191:1987–97.Google Scholar

  • 25.

    Quandt D, Hoff H, Rudolph M, Fillatreau S, Brunner-Weinzierl MC. A new role of CTLA-4 on B cells in thymus-dependent immune responses in vivo. J Immunol 2007;179:7316–24.Google Scholar

  • 26.

    Pioli C, Gatta L, Ubaldi V, Doria G. Inhibition of IgG1 and IgE production by stimulation of the B cell CTLA-4 receptor. J Immunol 2000;165:5530–6.Google Scholar

  • 27.

    Steiner K, Moosig F, Csernok E, Selleng K, Gross WL, Fleischer B, et al. Increased expression of CTLA-4 (CD152) by T and B lymphocytes in Wegener’s granulomatosis. Clin Exp Immunol 2001;126:143–50.Google Scholar

  • 28.

    Walker WE, Goldstein DR. Neonatal B cells suppress innate toll-like receptor immune responses and modulate alloimmunity. J Immunol 2007; 179:1700–10.Web of ScienceGoogle Scholar

  • 29.

    Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 2004;199:1567–75.Google Scholar

  • 30.

    Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 2005;54:1407–14.Google Scholar

  • 31.

    Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 2005;175:8392–400.Google Scholar

  • 32.

    Kolar P, Knieke K, Hegel JK, Quandt D, Burmester GR, Hoff H, et al. CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice. Arthritis Rheum 2009;60:123–32.Web of ScienceGoogle Scholar

  • 33.

    Wambre E, DeLong JH, James EA, LaFond RE, Robinson D, Kwok WW. Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J Allergy Clin Immunol 2012;129:544–51.Web of ScienceGoogle Scholar

  • 34.

    Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 2011;332:600–3.Web of ScienceGoogle Scholar

  • 35.

    Rudolph M, Hebel K, Miyamura Y, Maverakis E, Brunner-Weinzierl MC. Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo. J Immunol 2011;186:5580–9.Web of ScienceGoogle Scholar

  • 36.

    Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271–5.Google Scholar

  • 37.

    Kolar P, Hoff H, Maschmeyer P, Burmester GR, Brunner-Weinzierl MC. CTLA-4 (CD152) blockade does not cause a pro-inflammatory cytokine profile in regulatory T cells. Clin Exp Rheumatol 2011;29:254–60.Google Scholar

  • 38.

    Gieseler S, Brunner Weinzierl MC. Kinder zeigen erhöhtes Infektionsrisiko unter Intensivtherapie. Deutscher Ärzte-Verlag DIVI 2012;3:64–7.Google Scholar

  • 39.

    Hebel K, Rudolph M, Kosak B, Chang HD, Butzmann J, Brunner-Weinzierl MC. IL-1β and TGF-β act antagonistically in induction and differentially in propagation of human proinflammatory precursor CD4+ T cells. J Immunol 2011;187:5627–35.Web of ScienceGoogle Scholar

  • 40.

    Darrasse-Jeze G, Marodon G, Salomon BL, Catala M, Klatzmann D. Ontogeny of CD4+CD25+ regulatory/suppressor T cells in human fetuses. Blood 2005;105:4715–21.Google Scholar

  • 41.

    Mold JE, Venkatasubrahmanyam S, Burt TD, Michaelsson J, Rivera JM, Galkina SA, et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science 2010;330:1695–9.Web of ScienceGoogle Scholar

About the article

Korrespondenz: Prof. Dr. Monika C. Brunner-Weinzierl, Experimentelle Pädiatrie und Neonatalogie, Universitätskinderklinik, Universitätsklinikum Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Deutschland, Tel.: 0391/6724003, Fax: 0391/6724202


Received: 2013-03-05

Accepted: 2013-03-27

Published Online: 2013-05-07

Published in Print: 2013-06-01


Citation Information: Laboratoriumsmedizin, Volume 37, Issue 3, Pages 123–129, ISSN (Online) 1439-0477, ISSN (Print) 0342-3026, DOI: https://doi.org/10.1515/labmed-2012-0061.

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