Die Dynamik der angeborenen und adaptiven Immunantwort

Appendices

Aufgaben

1 11.1 Richtig oder falsch

Die Immunantwort ist ein dynamischer Prozess, der mit einer antigenunabhängigen Reaktion beginnt und konzentrierter und wirkungsvoller wird, sobald sie eine Antigenspezifität entwickelt. Sobald sich das adaptive Immunsystem entwickelt, ist eine einzige Art von Reaktion in der Lage, jeden Typ von Krankheitserreger zu beseitigen.

1 11.2 Multiple Choice

Welche Aussage trifft nicht zu?

• A. Die Produktion von IL-12 und IL-18 durch Makrophagen und dendritische Zellen löst die Sekretion von IFN-γ durch ILC1-Zellen aus, wodurch intrazelluläre Pathogene wirksamer abgetötet werden können.

• B. ILC3-Zellen werden durch thymusstromales Lymphopoetin (TSLP) aktiviert, das STAT5 aktiviert und die Produktion von IL-17 auslöst.

• C. Molekulare Muster, die üblicherweise bei Helminthen vorkommen, aktivieren die Produktion von IL-33 und IL-25, wodurch wiederum ILC2-Zellen aktiviert werden, die Schleimproduktion der Becherzellen und die Kontraktion der mucosalen glatten Muskulatur anzuregen.

• D. Von ILC3-Zellen erzeugtes IL-22 wirkt auf Epithelzellen, aktiviert deren Produktion von antimikrobiellen Peptiden und fördert die Verstärkung der Integrität von Barrieren.

1 11.3 Bitte zuordnen

Welches der folgenden Proteine hat welche Wirkung auf die Wanderung der T-Zellen?

A.	CXCR5 _____	i.	interagiert mit P- und E-Selektin, wird von aktivierten Endothelzellen exprimiert
B.	PSGL-1 _____	ii.	durch Bindung von CXCL13 werden TFH-Zellen in B-Zell-Follikel gelenkt
C.	FucT-VII _____	iii.	interagiert mit VCAM-1 und löst so die Extravasation der T-Effektorzellen aus
D.	VLA-4 _____	iv.	notwendig für die Produktion von P-und E-Selektin

1 11.4 Bitte ergänzen

Die Expression selektiver Adhäsionsmoleküle durch T-Effektorzellen trägt dazu bei, dass sie sich auf verschiedene Kompartimente verteilen. So induzieren beispielsweise T-Zellen, die in den GALT ihr Priming durchlaufen haben, die Expression des _______-Integrins, das an _______ bindet, welches wiederum von den Endothelzellen der Darmschleimhaut konstitutiv exprimiert wird. Diese T-Zellen exprimieren auch den Chemokinrezeptor _______, der T-Zellen über einen _______-Gradienten zur Lamina propria unterhalb des Dünndarmepithels lenkt. Diese Kompartimentierung ist nicht auf den Darm beschränkt, sondern kommt auch in anderen Organen vor, etwa in der Haut. So bindet beispielsweise die glykosylierte Form von PSGL-1, _______, an _______ auf Gefäßendothelien in der Haut.

1 11.5 Multiple Choice

Welche der folgenden Aussagen über die Aktivierung der T_H1-Makrophagen trifft nicht zu?

• A. Der CD40-Ligand macht den Makrophagen für die Reaktion auf IFN-γ empfindlicher.

• B. LT-α kann den CD40-Liganden bei der Makrophagenaktivierung ersetzen.

• C. Aktivierte T_H1-Zellen wirken der TNFR1-Aktivierung entgegen.

• D. Makrophagen werden durch geringe Mengen an bakteriellem LPS für IFN-γ empfindlicher.

1 11.6 Kurze Antwort

Wie stimulieren M2-Makrophagen die Kollagenproduktion zur Unterstützung der Reparatur von Geweben?

1 11.7 Multiple Choice

Welche der folgenden Aussagen trifft für Immunantworten vom Typ 3 nicht zu?

• A. Die primären angeborenen Effektorzellen sind die Neutrophilen, die von CXCL8 und CXCL2 rekrutiert werden und durch Einwirkung von G-CSF und GM-CSF eine erhöhte Produktionsrate haben.

• B. Im Zustand der Homöostase kommen die T_H17-Zellen fast ausschließlich in der Darmschleimhaut vor.

• C. IL-17 ist das zentrale Cytokin.

• D. Durch die Produktion von IL-22 werden die Erzeugung antimikrobieller Peptide, die Proliferation von Epithelzellen und das Ablösen der natürlichen Killerzellen angeregt.

• E. IL-23 löst die Festlegung von naiven CD4⁺-T-Zellen auf die T_H17-Linie aus.

1 11.8 Multiple Choice

Welcher der folgenden Krankheitserreger kann unabhängig von der Unterstützung durch T-Zellen eine starke CD8⁺-T-Zell-Reaktion auslösen?

• A. Streptococcus pneumoniae

• B. lymphocytäres Choriomeningitisvirus (LCMV)

• C. Listeria monocytogenes

• D. Staphylococcus aureus

• E. Salmonella

• F. Toxoplasma

1 11.9 Bitte ergänzen

Während einer Immunantwort auf einen Krankheitserreger exprimieren aktivierte T-Zellen _______, eine Komponente des hochaffinen IL-2-Rezeptors, und schalten die Expression der IL-17-Rezeptorkomponente _______ ab. Die aktivierten Zellen erzeugen auch verschiedene Isoformen der Tyrosinphosphatase _______, die von allen hämatopoetischen Zellen exprimiert wird. Die Effektorgedächtniszellen und zentralen Gedächtniszellen entwickeln sich und unterscheiden sich in der starken Expression von _______ bei Ersteren und _______ bei Letzteren. Das Überleben der CD4⁺- und CD8⁺-T-Gedächtniszellen hängt von _______ ab, wobei das Überleben der CD8⁺-T-Gedächtniszellen zusätzlich von _______ abhängig ist.

1 11.10 Richtig oder falsch

CD27 ist ein Markermolekül von naiven B-Zellen und von T-Gedächtniszellen.

1 11.11 Kurze Antwort

Wie kann die Aktivierung des Inflammasoms zum Auslösen von Typ-1- und Typ-3-Immunantworten beitragen, während Typ-2-Reaktionen abgeschwächt werden?

1 11.12 Bitte zuordnen

Welches Cytokin gehört zu welchem STAT-Faktor?

A.	IL-4 und IL-13 _____	i.	STAT3
B.	IL-12 _____	ii.	STAT4
C.	IL-23 _____	iii.	STAT5
D.	TSLP, IL-2 und IL-7 _____	iv.	STAT6

Literatur

1.1 Literatur zu den einzelnen Abschnitten

1.1.1 Abschnitt 11.1.1

• ■ Mandell, G., Bennett, J., and Dolin, R. (eds): Principles and Practice of Infectious Diseases, 5th edu. New York, Churchill Livingstone, 2000.

• ■ Zhang, S.Y., Jouanguy, E., Sancho-Shimizu, V., von Bernuth, H., Yang, K., Abel, L., Picard, C., Puel, A., and Casanova, J.L.: Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses. Immunol. Rev. 2007, 220:225–236.

1.1.2 Abschnitt 11.1.2

• ■ Bernink, J., Mjösberg, J., and Spits, H.: Th1- and Th2-like subsets of innate lymphoid cells. Immunol. Rev. 2013, 252:133–138.

• ■ Fearon, D.T. and Locksley, R.M.: The instructive role of innate immunity in the acquired immune response. Science 1996, 272:50–53.

• ■ Gasteiger, G. and Rudensky, A.Y.: Interactions between innate and adaptive lymphocytes. Nat. Rev. Immunol. 2014, 14:631–639.

• ■ Janeway Jr., C.A.: The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol. Today 1992, 13:11–16.

• ■ McKenzie, A.N.J., Spits, H., and Eberl, G.: Innate lymphoid cells in inflammaion and immunity. Immunity 2014, 41:366–374.

• ■ Neill, D.R., Wong, S.H., Bellosi, A., Flynn, R.J., Daly, M., Langford, T.K., Bucks, C., Kane, C.M., Fallon, P.G., Pannell, R., et al.: Nuocytes represent a new innate effecor leukocyte that mediates type-2 immunity. Nature 2010, 464:1367–1370.

• ■ Oliphant, C.J., Hwang, Y.Y., Walker, J.A., Salimi, M., Wong, S.H., Brewer, J.M., Englezakis, A., Barlow, J.L., Hams, E., Scanlon, S.T., et al.: MHCII-mediated dialog between group 2 innate lymphoid cells and CD4⁺ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 2014, 41:283–295.

• ■ Walker, J.A., Barlow, J.L., and McKenzie, A.N.J.: Innate lymphoid cells—how did we miss them? Nat. Rev. Immunol. 2013, 13:75–87.

1.1.3 Abschnitt 11.2.1

• ■ Griffith, J.W., Sokol, C.L., and Luster, A.D.: Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 2014, 32:659–702.

• ■ Hidalgo, A., Peired, A.J., Wild, M.K., Vestweber, D., and Frenette, P.S.: Complete identification of E-selectin ligands on neutrophils reveals distinct functions of PSGL-1, ESL-1, and CD44. Immunity 2007, 26:477–489.

• ■ MacKay, C.R., Marston, W., and Dudler, L.: Altered patterns of T-cell migration through lymph nodes and skin following antigen challenge. Eur. J. Immunol. 1992, 22:2205–2210.

• ■ Mantovani, A., Bonecchi, R., and Locati, M.: Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat. Rev. Immunol. 2006, 6:907–918.

• ■ Mueller, S.N., Gebhardt, T., Carbone, F.R., and Heath, W.R.: Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 2013, 31:137–161.

• ■ Sallusto, F., Kremmer, E., Palermo, B., Hoy, A., Ponath, P., Qin, S., Forster, R., Lipp, M., and Lanzavecchia, A.: Switch in chemokine receptor expression upon TCR stimulation reveals novel homing potential for recently activated T cells. Eur. J. Immunol. 1999, 29:2037–2045.

1.1.4 Abschnitt 11.2.2

• ■ Jenkins, M.K., Khoruts, A., Ingulli, E., Mueller, D.L., McSorley, S.J., Reinhardt, R.L., Itano, A., and Pape, K. A.: In vivo activation of antigen-specific CD4 T cells. Annu. Rev. Immunol. 2001, 19:23–45.

1.1.5 Abschnitt 11.2.3

• ■ Bekker, L.G., Freeman, S., Murray, P.J., Ryffel, B., and Kaplan, G.: TNF-α controls intracellular mycobacterial growth by both inducible nitric oxide synthase-dependent and inducible nitric oxide synthase-independent pathways. J. Immunol. 2001, 166:6728–6734.

• ■ Ehlers, S., Kutsch, S., Ehlers, E.M., Benini, J., and Pfeffer, K.: Lethal granuloma disintegration in mycobacteria-infected TNFRp55^–/– mice is dependent on T cells and IL-12. J. Immunol. 2000, 165:483–492.

• ■ Hsieh, C.S., Macatonia, S.E., Tripp, C.S., Wolf, S.F., O’Garra, A., and Murphy, K.M.: Development of T_H1 CD4⁺ T cells through IL-12 produced by Listeria-induced macrophages. Science 1993, 260:547–549.

• ■ Muñoz-Fernández, M.A., Fernández, M.A., and Fresno, M.: Synergism between tumor necrosis factor-α and interferon-γ on macrophage activation for the killing of intracellular Trypanosoma cruzi through a nitric oxide-dependent mechanism. Eur. J. Immunol. 1992, 22:301–307.

• ■ Murray, P.J. and Wynn, T.A.: Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011, 11:723–737.

• ■ Stout, R.D., Suttles, J., Xu, J., Grewal, I.S., and Flavell, R.A.: Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. J. Immunol. 1996, 156:8–11.

1.1.6 Abschnitt 11.2.4

• ■ Duffield, J.S.: The inflammatory macrophage: a story of Jekyll and Hyde. Clin. Sci. 2003, 104:27–38.

• ■ Labow, R.S., Meek, E., and Santerre, J.P.: Model systems to assess the destructive potential of human neutrophils and monocyte-derived macrophages during the acute and chronic phases of inflammation. J. Biomed. Mater. Res. 2001, 54:189–197.

• ■ Wigginton, J.E. and Kirschner, D.: A model to predict cell-mediated immune regulatory mechanisms during human infection with Mycobacterium tuberculosis. J. Immunol. 2001, 166:1951–1967.

1.1.7 Abschnitt 11.2.5

• ■ James, D.G.: A clinicopathological classification of granulomatous disorders. Postgrad. Med. J. 2000, 76:457–465.

1.1.8 Abschnitt 11.2.6

• ■ Berberich, C., Ramirez-Pineda, J.R., Hambrecht, C., Alber, G., Skeiky, Y.A., and Moll, H.: Dendritic cell (DC)-based protection against an intracellular pathogen is dependent upon DC-derived IL-12 and can be induced by molecularly defined antigens. J. Immunol. 2003, 170:3171–3179.

• ■ Biedermann, T., Zimmermann, S., Himmelrich, H., Gumy, A., Egeter, O., Sakrauski, A.K., Seegmuller, I., Voigt, H., Launois, P., Levine, A.D., et al.: IL-4 instructs T_H1 responses and resistance to Leishmania major in susceptible BALB/c mice. Nat. Immunol. 2001, 2:1054–1060.

• ■ Neighbors, M., Xu, X., Barrat, F.J., Ruuls, S.R., Churakova, T., Debets, R., Bazan, J.F., Kastelein, R.A., Abrams, J.S., and O’Garra, A.: A critical role for interleukin 18 in primary and memory effector responses to Listeria monocytogenes that extends beyond its effects on interferon gamma production. J. Exp. Med. 2001, 194:343–354.

1.1.9 Abschnitt 11.2.7

• ■ Artis, D. and Grencis, R.K.: The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol. 2008, 1:252–264.

• ■ Fallon, P.G., Ballantyne, S.J., Mangan, N.E., Barlow, J.L., Dasvarma, A., Hewett, D.R., McIlgorm, A., Jolin, H.E., and McKenzie, A.N.J.: Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 2006, 203:1105–1116.

• ■ Finkelman, F.D., Shea-Donohue, T., Goldhill, J., Sullivan, C.A., Morris, S.C., Madden, K.B., Gauser, W.C., and Urban Jr., J.F.: Cytokine regulation of host defense against parasitic intestinal nematodes. Annu. Rev. Immunol. 1997, 15:505–533.

• ■ Humphreys, N.E., Xu, D., Hepworth, M.R., Liew, F.Y., and Grencis, R.K.: IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 2008, 180:2443–2449.

• ■ Liang, H.-E., Reinhardt, R.L., Bando, J.K., Sullivan, B.M., Ho, I.-C., and Locksley, R.M.: Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 2012, 13:58–66.

• ■ Maizels, R.M., Pearce, E.J., Artis, D., Yazdanbakhsh, M., and Wynn, T.A.: Regulation of pathogenesis and immunity in helminth infections. J. Exp. Med. 2009, 206:2059–2066.

• ■ Ohnmacht, C., Schwartz, C., Panzer, M., Schiedewitz, I., Naumann, R., and Voehringer, D.: Basophils orchestrate chronic allergic dermatitis and protective immunity against helminths. Immunity 2010, 33:364–374.

• ■ Saenz, S.A., Noti, M., and Artis, D.: Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol. 2010, 31:407–413.

• ■ Sullivan, B.M. and Locksley, R.M.: Basophils: a nonredundant contributor to host immunity. Immunity 2009, 30:12–20.

• ■ Van Dyken, S.J. and Locksley, R.M.: Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu. Rev. Immunol. 2013, 31:317–343.

1.1.10 Abschnitt 11.2.8

• ■ Aujla, S.J., Chan, Y.R., Zheng, M., Fei, M., Askew, D.J., Pociask, D.A., Reinhart, T.A., Mcallister, F., Edeal, J., Gaus, K., et al.: IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat. Med. 2008, 14:275–281.

• ■ Fossiez, F., Djossou, O., Chomarat, P., Flores-Romo, L., Ait-Yahia, S., Maat, C., Pin, J.J., Garrone, P., Garcia, E., Saeland, S., et al.: T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 1996, 183:2593–2603.

• ■ Happel, K.I., Zheng, M., Young, E., Quinton, L.J., Lockhart, E., Ramsay, A.J., Shellito, J.E., Schurr, J.R., Bagby, G.J., Nelson, S., et al.: Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 2003, 170:4432–4436.

• ■ LeibundGut-Landmann, S., Gross, O., Robinson, M.J., Osorio, F., Slack, E.C., Tsoni, S.V., Schweighoffer, E., Tybulewicz, V., Brown, G.D., Ruland, J., et al.: Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 2007, 8:630–638.

• ■ Ouyang, W., Kolls, J.K., and Zheng, Y.: The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 2008, 28:454–467.

• ■ Romani, L.: Immunity to fungal infections. Nat. Rev. Immunol. 2011, 11:275–288.

• ■ Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A., and Artis, D.: CD4⁺ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 2011, 34:122–134.

• ■ Zheng, Y., Valdez, P.A., Danilenko, D.M., Hu, Y., Sa, S.M., Gong, Q., Abbas, A.R., Modrusan, Z., Ghilardi, N., De Sauvage, F.J., et al.: Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 2008, 14:282–289.

1.1.11 Abschnitt 11.2.9

• ■ Cua, D.J., Sherlock, J., Chen, Y., Murphy, C.A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., et al.: Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421:744–748.

• ■ Ghilardi, N., Kljavin, N., Chen, Q., Lucas, S., Gurney, A.L., and De Sauvage, F.J.: Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J. Immunol. 2004, 172:2827–2833.

• ■ Park, A.Y., Hondowics, B.D., and Scott, P.: IL-12 is required to maintain a Th1 response during Leishmania major infection. J. Immunol. 2000, 165:896–902.

• ■ Yap, G., Pesin, M., and Sher, A.: Cutting edge: IL-12 is required for the maintenance of IFN-γ production in T cells mediating chronic resistance to the intracellular pathogen Toxoplasma gondii. J. Immunol. 2000, 165:628–631.

1.1.12 Abschnitt 11.2.10

• ■ Guo, L., Junttila, I.S., and Paul, W.E.: Cytokine-induced cytokine production by conventional and innate lymphoid cells. Trends Immunol. 2012, 33:598–606.

• ■ Kohno, K., Kataoka, J., Ohtsuki, T., Suemoto, Y., Okamoto, I., Usui, M., Ikeda, M., and Kurimoto, M.: IFN-gamma-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J. Immunol. 1997, 158:1541–1550.

1.1.13 Abschnitt 11.2.11

• ■ Basu, R., Hatton, R.D., and Weaver, C.T.: The Th17 family: flexibility follows function. Immunol. Rev. 2013, 252:89–103.

• ■ Lee, S.-J., McLachlan, J.B., Kurtz, J.R., Fan, D., Winter, S.E., Bäumler, A.J., Jenkins, M.K., and McSorley, S.J.: Temporal expression of bacterial proteins instructs host CD4 T cell expansion and Th17 development. PLoS Pathog. 2012, 8:e1002499.

• ■ Lee, Y.K., Turner, H., Maynard, C.L., Oliver, J.R., Chen, D., Elson, C.O., and Weaver, C.T.: Late developmental plasticity in the T helper 17 lineage. Immunity 2009, 30:92–107.

• ■ Murphy, K.M. and Stockinger, B.: Effector T cell plasticity: flexibility in the face of changing circumstances. Nat. Immunol. 2010, 11:674–680.

• ■ O’Shea, J.J. and Paul, W.E.: Mechanisms underlying lineage commitment and plasticity of helper CD4⁺ T cells. Science 2010, 327:1098–1102.

1.1.14 Abschnitt 11.2.12

• ■ Baize, S., Leroy, E.M., Georges-Courbot, M.C., Capron, M., Lansoud-Soukate, J., Debre, P., Fisher-Hoch, S.P., McCormick, J.B., and Georges, A.J.: Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat. Med. 1999, 5:423–426.

1.1.15 Abschnitt 11.2.13

• ■ Lertmemongkolchai, G., Cai, G., Hunter, C.A., and Bancroft, G.J.: Bystander activation of CD8 T cells contributes to the rapid production of IFN-γ in response to bacterial pathogens. J. Immunol. 2001, 166:1097–1105.

• ■ Rahemtulla, A., Fung-Leung, W.P., Schilham, M.W., Kundig, T.M., Sambhara, S.R., Narendran, A., Arabian, A., Wakeham, A., Paige, C.J., Zinkernagel, R.M., et al.: Normal development and function of CD8⁺ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 1991, 353:180–184.

• ■ Schoenberger, S.P., Toes, R.E., van der Voort, E.I., Offringa, R., and Melief, C.J.: T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 1998, 393:480–483.

• ■ Sun, J.C. and Bevan, M.J.: Defective CD8 T cell memory following acute infection without CD4 T-cell help. Science 2003, 300:339–349.

1.1.16 Abschnitt 11.2.14

• ■ Bouillet, P. and O’Reilly, L.A.: CD95, BIM and T cell homeostasis. Nat. Rev. Immunol. 2009, 9:514–519.

• ■ Chowdhury, D. and Lieberman, J.: Death by a thousand cuts: granzyme pathways of programmed cell death. Annu. Rev. Immunol. 2008, 26:389–420.

• ■ Siegel, R.M.: Caspases at the crossroads of immune-cell life and death. Nat. Rev. Immunol. 2006, 6:308–317.

• ■ Strasser, A.: The role of BH3-only proteins in the immune system. Nat. Rev. Immunol. 2005, 5:189–200.

1.1.17 Abschnitt 11.3.1

• ■ Black, F.L. and Rosen, L.: Patterns of measles antibodies in residents of Tahiti and their stability in the absence of re-exposure. J. Immunol. 1962, 88:725–731.

• ■ Hammarlund E., Lewis, M.W., Hanifin, J.M., Mori, M., Koudelka, C.W., and Slifka, M.K.: Antiviral immunity following smallpox virus infection: a case-control study. J. Virol. 2010, 84:12754–60.

• ■ Hammarlund, E., Lewis, M.W., Hansen, S.G., Strelow, L.I., Nelson, J.A., Sexton, G.J., Hanifin, J.M., and Slifka, M.K.: Duration of antiviral immunity after smallpox vaccination. Nat. Med. 2003, 9:1131–1137.

• ■ MacDonald, H.R., Cerottini, J.C., Ryser, J.E., Maryanski, J.L., Taswell, C., Widmer, M.B., and Brunner, K.T.: Quantitation and cloning of cytolytic T lymphocytes and their precursors. Immunol. Rev. 1980, 51:93–123.

• ■ Murali-Krishna, K., Lau, L.L., Sambhara, S., Lemonnier, F., Altman, J., and Ahmed, R.: Persistence of memory CD8 T cells in MHC class I-deficient mice. Science 1999, 286:1377–1381.

• ■ Seddon, B., Tomlinson, P., and Zamoyska, R.: Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat. Immunol. 2003, 4:680–686.

1.1.18 Abschnitt 11.3.2

• ■ Andersson, B.: Studies on the regulation of avidity at the level of the single antibody-forming cell: The effect of antigen dose and time after immunization. J. Exp. Med. 1970, 132:77–88.

• ■ Berek, C. and Milstein, C.: Mutation drift and repertoire shift in the maturation of the immune response. Immunol. Rev. 1987, 96:23–41.

• ■ Bergmann, B., Grimsholm, O., Thorarinsdottir, K., Ren, W., Jirholt, P., Gjertsson, I., and Mårtensson, I.L.: Memory B cells in mouse models. Scand. J. Immunol. 2013, 78:149–156.

• ■ Davie, J.M. and Paul, W.E.: Receptors on immunocompetent cells. V. Cellular correlates of the “maturation” of the immune response. J. Exp. Med. 1972, 135:660–674.

• ■ Eisen, H.N., and Siskind, G.W.: Variations in affinities of antibodies during the immune response. Biochemistry 1964, 3:996–1008.

• ■ Good-Jacobson, K.L. and Tarlinton, D.M.: Multiple routes to B-cell memory. Int. Immunol. 2012, 24:403–408.

• ■ Klein, U., Rajewsky, K., and Küppers, R.: Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 1998, 188:1679–1689.

• ■ Takemori, T., Kaji, T., Takahashi, Y., Shimoda, M., and Rajewsky, K.: Generation of memory B cells inside and outside germinal centers. Eur. J. Immunol. 2014, 44:1258–1264.

1.1.19 Abschnitt 11.3.3

• ■ Bende, R.J., van Maldegem, F., Triesscheijn, M., Wormhoudt, T.A., Guijt, R., and van Noesel, C.J.: Germinal centers in human lymph nodes contain reactivated memory B cells. J. Exp. Med. 2007, 204:2655–2665.

• ■ Dal Porto, J.M., Haberman, A.M., Kelsoe, G., and Shlomchik, M.J.: Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced. J. Exp. Med. 2002, 195:1215–1221.

• ■ Goins, C.L., Chappell, C.P., Shashidharamurthy, R., Selvaraj, P., and Jacob, J.: Immune complex-mediated enhancement of secondary antibody responses. J. Immunol. 2010, 184:6293–6298.

• ■ Kaji, T., Furukawa, K., Ishige, A., Toyokura, I., Nomura, M., Okada, M., Takahashi, Y., Shimoda, M., and Takemori, T.: Both mutated and unmutated memory B cells accumulate mutations in the course of the secondary response and develop a new antibody repertoire optimally adapted to the secondary stimulus. Int. Immunol. 2013, 25:683–695.

1.1.20 Abschnitt 11.3.4

• ■ Hataye, J., Moon, J.J., Khoruts, A., Reilly, C., and Jenkins, M.K.: Naive and memory CD4⁺ T cell survival controlled by clonal abundance. Science 2006, 312:114–116.

• ■ Pagán, A.J., Pepper, M., Chu, H.H., Green, J.M., and Jenkins, M.K.: CD28 promotes CD4⁺ T cell clonal expansion during infection independently of its YMNM and PYAP motifs. J. Immunol. 2012, 189:2909–2917.

• ■ Pepper, M., Pagán, A.J., Igyártó, B.Z., Taylor, J.J., and Jenkins, M.K.: Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 2011, 35:583–595.

1.1.21 Abschnitt 11.3.5

• ■ Akondy, R.S., Monson, N.D., Miller, J.D., Edupuganti, S., Teuwen, D., Wu, H., Quyyumi, F., Garg, S., Altman, J.D., Del Rio, C., et al.: The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8⁺ T cell response. J. Immunol. 2009, 183:7919–7930.

• ■ Bradley, L.M., Atkins, G.G., and Swain, S.L.: Long-term CD4⁺ memory T cells from the spleen lack MEL-14, the lymph node homing receptor. J. Immunol. 1992, 148:324–331.

• ■ Kaech, S.M., Hemby, S., Kersh, E., and Ahmed, R.: Molecular and functional profiling of memory CD8 T cell differentiation. Cell 2002, 111:837–851.

• ■ Kassiotis, G., Garcia, S., Simpson, E., and Stockinger, B.: Impairment of immunological memory in the absence of MHC despite survival of memory T cells. Nat. Immunol. 2002, 3:244–250.

• ■ Ku, C.C., Murakami, M., Sakamoto, A., Kappler, J., and Marrack, P.: Control of homeostasis of CD8⁺ memory T cells by opposing cytokines. Science 2000, 288:675–678.

• ■ Rogers, P.R., Dubey, C., and Swain, S.L.: Qualitative changes accompany memory T cell generation: faster, more effective responses at lower doses of antigen. J. Immunol. 2000, 164:2338–2346.

• ■ Wherry, E.J., Teichgraber, V., Becker, T.C., Masopust, D., Kaech, S.M., Antia, R., von Andrian, U.H., and Ahmed, R.: Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 2003, 4:225–234.

1.1.22 Abschnitt 11.3.6

• ■ Cerottini, J.C., Budd, R.C., and MacDonald, H.R.: Phenotypic identification of memory cytolytic T lymphocytes in a subset of Lyt-2+ cells. Ann. N. Y. Acad. Sci. 1988, 532:68–75.

• ■ Kaech, S.M., Tan, J.T., Wherry, E.J., Konieczny, B.T., Surh, C.D., and Ahmed, R.: Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 2003, 4:1191–1198.

• ■ Lanzavecchia, A. and Sallusto, F.: Understanding the generation and function of memory T cell subsets. Curr. Opin. Immunol. 2005, 17:326–332.

• ■ Mueller, S.N., Gebhardt, T., Carbone, F.R., and Heath, W.R.: Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 2012, 31:137–161.

• ■ Sallusto, F., Geginat, J., and Lanzavecchia, A.: Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 2004, 22:745–763.

• ■ Sallusto, F., Lenig, D., Forster, R., Lipp, M., and Lanzavecchia, A.: Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999, 401:708–712.

• ■ Skon, C.N., Lee, J.Y., Anderson, K.G., Masopust, D., Hogquist, K. A., and Jameson, S.C.: Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8⁺ T cells. Nat. Immunol. 2013, 14:1285–1293.

1.1.23 Abschnitt 11.3.7

• ■ Bourgeois, C. and Tanchot, C.: CD4 T cells are required for CD8 T cell memory generation. Eur. J. Immunol. 2003, 33:3225–3231.

• ■ Bourgeois, C., Rocha, B., and Tanchot, C.: A role for CD40 expression on CD8 T cells in the generation of CD8 T cell memory. Science 2002, 297:2060–2063.

• ■ Janssen, E.M., Lemmens, E.E., Wolfe, T., Christen, U., von Herrath, M.G., and Schoenberger, S.P.: CD4 T cells are required for secondary expansion and memory in CD8 T lymphocytes. Nature 2003, 421:852–856.

• ■ Shedlock, D.J. and Shen, H.: Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 2003, 300:337–339.

• ■ Sun, J.C., Williams, M.A., and Bevan, M.J.: CD4 T cells are required for the maintenance, not programming, of memory CD8 T cells after acute infection. Nat. Immunol. 2004, 5:927–933.

• ■ Tanchot, C. and Rocha, B.: CD8 and B cell memory: same strategy, same signals. Nat. Immunol. 2003, 4:431–432.

• ■ Williams, M.A., Tyznik, A.J., and Bevan, M.J.: Interleukin-2 signals during priming are required for secondary expansion of CD8 memory T cells. Nature 2006, 441:890–893.

1.1.24 Abschnitt 11.3.8

• ■ Fazekas de St Groth, B. and Webster, R.G.: Disquisitions on original antigenic sin. I. Evidence in man. J. Exp. Med. 1966, 140:2893–2898.

• ■ Fridman, W.H.: Regulation of B cell activation and antigen presentation by Fc receptors. Curr. Opin. Immunol. 1993, 5:355–360.

• ■ Klenerman, P. and Zinkernagel, R.M.: Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 1998, 394:482–485.

• ■ Mongkolsapaya, J., Dejnirattisai, W., Xu, X.N., Vasanawathana, S., Tangthawornchaikul, N., Chairunsri, A., Sawasdivorn, S., Duangchinda, T., Dong, T., Rowland-Jones, S., et al.: Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat. Med. 2003, 9:921–927.

• ■ Pollack, W., Gorman, J.G., Freda, V.J., Ascari, W.Q., Allen, A.E., and Baker, W.J.: Results of clinical trials of RhoGAm in women. Transfusion 1968, 8:151–153.

• ■ Zehn, D., Turner, M.J., Lefrançois, L., and Bevan, M.J.: Lack of original anti-genic sin in recall CD8⁺ T cell responses. J. Immunol. 2010, 184:6320–6326.