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Immunologic Research
Published in: Immunologic Research 2-3/2009

01-12-2009

Understanding the focused CD4 T cell response to antigen and pathogenic organisms

Authors: Jason M. Weaver, Andrea J. Sant

Published in: Immunologic Research | Issue 2-3/2009

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Abstract

Immunodominance is a term that reflects the final, very limited peptide specificity of T cells that are elicited during an immune response. Recent experiments in our laboratory compel us to propose a new paradigm for the control of immunodominance in CD4 T cell responses, stating that immunodominance is peptide-intrinsic and is dictated by the off-rate of peptides from MHC class II molecules. Our studies have revealed that persistence of peptide:class II complexes both predicts and controls CD4 T cell immunodominance and that this parameter can be rationally manipulated to either promote or eliminate immune responses. Mechanistically, we have determined that DM editing in APC is a key event that is influenced by the kinetic stability of class II:peptide complexes and that differential persistence of complexes also impacts the expansion phase of the immune response. These studies have important implications for rational vaccine design and for understanding the immunological mechanisms that limit the specificity of CD4 T cell responses.
Literature
1.
Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol. 1993;11:729–66.PubMed
2.
Deng H, Fosdick L, Sercarz E. The involvement of antigen processing in determinant selection by class II MHC and its relationship to immunodominance. APMIS. 1993;101:655–62.PubMed
3.
Sant AJ, Chaves FA, Jenks SA, Richards KA, Menges P, Weaver JM, et al. The relationship between immunodominance, DM editing, and the kinetic stability of MHC class II:peptide complexes. Immunol Rev. 2005;207:261–78.PubMed
4.
Fairchild PJ. Reversal of immunodominance among autoantigenic T-cell epitopes. Autoimmunity. 1999;30:209–21.PubMed
5.
Blum JS, Ma C, Kovats S. Antigen-presenting cells and the selection of immunodominant epitopes. Crit Rev Immunol. 1997;17:411–7.PubMed
6.
Yewdell JW, Del Val M. Immunodominance in TCD8+ responses to viruses: cell biology, cellular immunology, and mathematical models. Immunity. 2004;21:149–53.PubMed
7.
Chen W, McCluskey J. Immunodominance and immunodomination: critical factors in developing effective CD8+ T-cell-based cancer vaccines. Adv Cancer Res. 2006;95:203–47.PubMed
8.
Yewdell JW. Confronting complexity: real-world immunodominance in antiviral CD8+ T cell responses. Immunity. 2006;25:533–43.PubMed
9.
Nikcevich KM, Kopielski D, Finnegan A. Interference with the binding of a naturally processed peptide to class II alters the immunodominance of T cell epitopes in vivo. J Immunol. 1994;153:1015–26.PubMed
10.
Thayer WP, Kraft JR, Tompkins SM, Moore JC, Jensen PE. Assessment of the role of determinant selection in genetic control of the immune response to insulin in H-2b mice. J Immunol. 1999;163:2549–54.PubMed
11.
Ma C, Whiteley PE, Cameron PM, Freed DC, Pressey A, Chen SL, et al. Role of APC in the selection of immunodominant T cell epitopes. J Immunol. 1999;163:6413–23.PubMed
12.
Moudgil KD, Sercarz EE, Grewal IS. Modulation of the immunogenicity of antigenic determinants by their flanking residues. Immunol Today. 1998;19:217–20.PubMed
13.
Gapin L, Cabaniols JP, Cibotti R, Ojcius DM, Kourilsky P, Kanellopoulos JM. Determinant selection for T-cell tolerance in HEL-transgenic mice: dissociation between immunogenicity and tolerogenicity. Cell Immunol. 1997;177:77–85.PubMed
14.
Yewdell JW, Bennink JR. Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Annu Rev Immunol. 1999;17:51–88.PubMed
15.
Safley SA, Jensen PE, Reay PA, Ziegler HK. Mechanisms of T cell epitope immunodominance analyzed in murine listeriosis. J Immunol. 1995;155:4355–66.PubMed
16.
Moudgil KD, Deng H, Nanda NK, Grewal IS, Ametani A, Sercarz EE. Antigen processing and T cell repertoires as crucial aleatory features in induction of autoimmunity. J Autoimmun. 1996;9:227–34.PubMed
17.
Adorini L, Muller S, Cardinaux F, Lehmann PV, Falcioni F, Nagy ZA. In vivo competition between self peptides and foreign antigens in T-cell activation. Nature. 1988;334:623–5.PubMed
18.
Liu Z, Williams KP, Chang YH, Smith JA. Immunodominance: a single amino acid substitution within an antigenic site alters intramolecular selection of T cell determinants. J Immunol. 1993;151:1852–8.PubMed
19.
Vidard L, Rock KL, Benacerraf B. The generation of immunogenic peptides can be selectively increased or decreased by proteolytic enzyme inhibitors. J Immunol. 1991;147:1786–91.PubMed
20.
Schneider SC, Ohmen J, Fosdick L, Gladstone B, Guo J, Ametani A, et al. Cutting Edge: introduction of an endopeptidase cleavage motif into a determinant flanking region of hen egg lysozyme results in enhanced T cell determinant display. J Immunol. 2000;165:20–3.PubMed
21.
Melton SJ, Landry SJ. Three dimensional structure directs T-cell epitope dominance associated with allergy. Clin Mol Allergy. 2008;6:9.PubMed
22.
Mirano-Bascos D, Tary-Lehmann M, Landry SJ. Antigen structure influences helper T-cell epitope dominance in the human immune response to HIV envelope glycoprotein gp120. Eur J Immunol. 2008;38:1231–7.PubMed
23.
Carmicle S, Steede NK, Landry SJ. Antigen three-dimensional structure guides the processing and presentation of helper T-cell epitopes. Mol Immunol. 2007;44:1159–68.PubMed
24.
Dai G, Carmicle S, Steede NK, Landry SJ. Structural basis for helper T-cell and antibody epitope immunodominance in bacteriophage T4 Hsp10. Role of disordered loops. J Biol Chem. 2002;277:161–8.PubMed
25.
Phan UT, Arunachalam B, Cresswell P. Gamma-interferon-inducible lysosomal thiol reductase (GILT). Maturation, activity, and mechanism of action. J Biol Chem. 2000;275:25907–14.PubMed
26.
Landry SJ. Helper T-cell epitope immunodominance associated with structurally stable segments of hen egg lysozyme and HIV gp120. J Theor Biol. 2000;203:189–201.PubMed
27.
Nanda NK, Sant AJ. DM determines the cryptic and immunodominant fate of T cell epitopes. J Exp Med. 2000;192:781–8.PubMed
28.
Sant AJ, Beeson C, McFarland B, Cao J, Ceman S, Bryant PW, et al. Individual hydrogen bonds play a critical role in MHC class II: peptide interactions: implications for the dynamic aspects of class II trafficking and DM-mediated peptide exchange. Immunol Rev. 1999;172:239–53.PubMed
29.
Brocke P, Garbi N, Momburg F, Hammerling GJ. HLA-DM, HLA-DO and tapasin: functional similarities and differences. Curr Opin Immunol. 2002;14:22–9.PubMed
30.
Jensen PE, Weber DA, Thayer WP, Chen X, Dao CT. HLA-DM and the MHC class II antigen presentation pathway. Immunol Res. 1999;20:195–205.PubMed
31.
Kropshofer H, Hammerling GJ, Vogt AB. How HLA-DM edits the MHC class II peptide repertoire: survival of the fittest? Immunol Today. 1997;18:77–82.PubMed
32.
Busch R, Rinderknecht CH, Roh S, Lee AW, Harding JJ, Burster T, et al. Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression. Immunol Rev. 2005;207:242–60.PubMed
33.
Sadegh-Nasseri S, Chen M, Narayan K, Bouvier M. The convergent roles of tapasin and HLA-DM in antigen presentation. Trends Immunol. 2008;29:141–7.PubMed
34.
Lightstone L, Hargreaves R, Bobek G, Peterson M, Aichinger G, Lombardi G, et al. In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM. Proc Natl Acad Sci USA. 1997;94:5772–7.PubMed
35.
van Ham SM, Gruneberg U, Malcherek G, Broker I, Melms A, Trowsdale J. Human histocompatibility leukocyte antigen (HLA)-DM edits peptides presented by HLA-DR according to their ligand binding motifs. J Exp Med. 1996;184:2019–24.PubMed
36.
Drover S, Kovats S, Masewicz S, Blum JS, Nepom GT. Modulation of peptide-dependent allospecific epitopes on HLA-DR4 molecules by HLA-DM. Hum Immunol. 1998;59:77–86.PubMed
37.
Katz JF, Stebbins C, Appella E, Sant AJ. Invariant chain and DM edit self-peptide presentation by major histocompatibility complex (MHC) class II molecules. J Exp Med. 1996;184:1747–53.PubMed
38.
Kropshofer H, Vogt AB, Moldenhauer G, Hammer J, Blum JS, Hammerling GJ. Editing of the HLA-DR-peptide repertoire by HLA-DM. EMBO J. 1996;15:6144–54.PubMed
39.
Vogt AB, Kropshofer H, Hammerling GJ. How HLA-DM affects the peptide repertoire bound to HLA-DR molecules. Hum Immunol. 1997;54:170–9.PubMed
40.
Arndt SO, Vogt AB, Hammerling GJ, Kropshofer H. Selection of the MHC class II-associated peptide repertoire by HLA-DM. Immunol Res. 1997;16:261–72.PubMed
41.
Lovitch SB, Petzold SJ, Unanue ER. Cutting edge: H-2DM is responsible for the large differences in presentation among peptides selected by I-Ak during antigen processing. J Immunol. 2003;171:2183–6.PubMed
42.
Lazarski CA, Chaves FA, Sant AJ. The impact of DM on MHC class II-restricted antigen presentation can be altered by manipulation of MHC-peptide kinetic stability. J Exp Med. 2006;203:1319–28.PubMed
43.
Sant AJ, Chaves FA, Krafcik FR, Lazarski CA, Menges P, Richards K, et al. Immunodominance in CD4 T-cell responses: implications for immune responses to influenza virus and for vaccine design. Expert Rev Vaccines. 2007;6:357–68.PubMed
44.
Brett SJ, Cease KB, Berzofsky JA. Influences of antigen processing on the expression of the T cell repertoire. Evidence for MHC-specific hindering structures on the products of processing. J Exp Med. 1988;168:357–73.PubMed
45.
Zhu H, Liu K, Cerny J, Imoto T, Moudgil KD. Insertion of the dibasic motif in the flanking region of a cryptic self-determinant leads to activation of the epitope-specific T cells. J Immunol. 2005;175:2252–60.PubMed
46.
Brown SA, Stambas J, Zhan X, Slobod KS, Coleclough C, Zirkel A, et al. Clustering of Th cell epitopes on exposed regions of HIV envelope despite defects in antibody activity. J Immunol. 2003;171:4140–8.PubMed
47.
Adorini L, Appella E, Doria G, Nagy ZA. Mechanisms influencing the immunodominance of T cell determinants. J Exp Med. 1988;168:2091–104.PubMed
48.
Weaver JM, Lazarski CA, Richards KA, Chaves FA, Jenks SA, Menges PR, et al. Immunodominance of CD4 T cells to foreign antigens is peptide intrinsic and independent of molecular context: implications for vaccine design. J Immunol. 2008;181:3039–48.PubMed
49.
Lazarski CL, Chaves F, Jenks S, Wu S, Richards K, Weaver JM, et al. The kinetic stability of MHC class II:peptide complexes is a key parameter that dictates immunodominance. Immunity. 2005;23:29–40.PubMed
50.
Martineau P, Guillet JG, Leclerc C, Hofnung M. Expression of heterologous peptides at two permissive sites of the MalE protein: antigenicity and immunogenicity of foreign B-cell and T-cell epitopes. Gene. 1992;118:151.PubMed
51.
Lo-Man R, Martineau P, Hofnung M, Leclerc C. Induction of T cell responses by chimeric bacterial proteins expressing several copies of a viral T cell epitope. Eur J Immunol. 1993;23:2998–3002.PubMed
52.
Carson RT, Vignali KM, Woodland DL, Vignali DA. T cell receptor recognition of MHC class II-bound peptide flanking residues enhances immunogenicity and results in altered TCR V region usage. Immunity. 1997;7:387–99.PubMed
53.
Arnold PY, La Gruta NL, Miller T, Vignali KM, Adams PS, Woodland DL, et al. The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues. J Immunol. 2002;169:739–49.PubMed
54.
Bixler GS Jr, Atassi MZ. T cell recognition of myoglobin. Localization of the sites stimulating T cell proliferative responses by synthetic overlapping peptides encompassing the entire molecule. J Immunogenet. 1984;11:339–53.PubMed
55.
Berkower I, Matis LA, Buckenmeyer GK, Gurd FR, Longo DL, Berzofsky JA. Identification of distinct predominant epitopes recognized by myoglobin-specific T cells under the control of different Ir genes and characterization of representative T cell clones. J Immunol. 1984;132:1370–8.PubMed
56.
Reiner SL, Fowell DJ, Moskowitz NH, Swier K, Brown DR, Brown CR, et al. Control of Leishmania major by a monoclonal alpha beta T cell repertoire. J Immunol. 1998;160:884–9.PubMed
57.
Stetson DB, Mohrs M, Mallet-Designe V, Teyton L, Locksley RM. Rapid expansion and IL-4 expression by Leishmania-specific naive helper T cells in vivo. Immunity. 2002;17:191–200.PubMed
58.
Moudgil KD, Wang J, Yeung VP, Sercarz EE. Heterogeneity of the T cell response to immunodominant determinants within hen eggwhite lysozyme of individual syngeneic hybrid F1 mice: implications for autoimmunity and infection. J Immunol. 1998;161:6046–53.PubMed
59.
Moudgil KD, Sekiguchi D, Kim SY, Sercarz EE. Immunodominance is independent of structural constraints: each region within hen eggwhite lysozyme is potentially available upon processing of native antigen. J Immunol. 1997;159:2574–9.PubMed
60.
Shimonkevitz R, Colon S, Kappler JW, Marrack P, Grey HM. Antigen recognition by H-2-restricted T cells. II. A tryptic ovalbumin peptide that substitutes for processed antigen. J Immunol. 1984;133:2067–74.PubMed
61.
McFarland BJ, Sant AJ, Lybrand TP, Beeson C. Ovalbumin(323–339) peptide binds to the major histocompatibility complex class II I-A(d) protein using two functionally distinct registers. Biochemistry. 1999;38:16663–70.PubMed
62.
Martineau P, Leclerc C, Hofnung M. Modulating the immunological properties of a linear B-cell epitope by insertion into permissive sites of the MalE protein. Mol Immunol. 1996;33:1345–58.PubMed
63.
Wouters S, Decroly E, Vandenbranden M, Shober D, Fuchs R, Morel V, et al. Occurrence of an HIV-1 gp160 endoproteolytic activity in low-density vesicles and evidence for a distinct density distribution from endogenously expressed furin and PC7/LPC convertases. FEBS Lett. 1999;456:97–102.PubMed
64.
Steiner DF. The proprotein convertases. Curr Opin Chem Biol. 1998;2:31–9.PubMed
65.
Glandieres JM, Hertzog M, Lazar N, Brakch N, Cohen P, Alpert B, et al. Kinetics of precursor cleavage at the dibasic sites. Involvement of peptide dynamics. FEBS Lett. 2002;516:75–9.PubMed
66.
Rholam M, Brakch N, Germain D, Thomas DY, Fahy C, Boussetta H, et al. Role of amino acid sequences flanking dibasic cleavage sites in precursor proteolytic processing. The importance of the first residue C-terminal of the cleavage site. Eur J Biochem. 1995;227:707–14.PubMed
67.
Chretien M. Endoproteolysis in health and diseases—implications of proprotein convertases (PCs). J Mol Med. 2005;83:842–3.PubMed
68.
Bachert C, Fimmel C, Linstedt AD. Endosomal trafficking and proprotein convertase cleavage of cis golgi protein GP73 produces marker for hepatocellular carcinoma. Traffic. 2007;8(10):1415–23.PubMed
69.
Richards RM, Lowy DR, Schiller JT, Day PM. Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection. Proc Natl Acad Sci USA. 2006;103:1522–7.PubMed
70.
Mayer G, Boileau G, Bendayan M. Sorting of furin in polarized epithelial and endothelial cells: expression beyond the Golgi apparatus. J Histochem Cytochem. 2004;52:567–79.PubMed
71.
Gammon G, Geysen HM, Apple RJ, Pickett E, Palmer M, Ametani A, et al. T cell determinant structure: cores and determinant envelopes in three mouse major histocompatibility complex haplotypes. J Exp Med. 1991;173:609–17.PubMed
72.
Weber DA, Evavold BD, Jensen PE. Enhanced dissociation of HLA-DR-bound peptides in the presence of HLA-DM. Science. 1996;274:618–20.PubMed
73.
Chaves FA, Richards KA, Torelli A, Wedekind J, Sant AJ. Peptide-binding motifs for the I-Ad MHC class II molecule: alternate pH-dependent binding behavior. Biochemistry. 2006;45:6426–33.PubMed
74.
Chaves FA, Sant AJ. Measurement of peptide dissociation from MHC class II molecules. Curr Protoc Immunol. 2007;Chapter 18:Unit 18 14.
75.
McFarland B, Katz JF, Beeson C, Sant AJ. Energetic asymmetry among hydrogen bonds in MHC class II:peptide complexes. Proc Natl Acad Sci USA. 2001;98:9231–6.PubMed
76.
Bandyopadhyay A, Arneson L, Beeson C, Sant AJ. The relative energetic contributions of dominant P1 pocket versus hydrogen bonding interactions to peptide:class II stability: implications for the mechanism of DM function. Mol Immunol. 2008;45:1248–57.PubMed
77.
Belmares MP, Busch R, Mellins ED, McConnell HM. Formation of two peptide/MHC II isomers is catalyzed differentially by HLA-DM. Biochemistry. 2003;42:838–47.PubMed
78.
Vogt AB, Kropshofer H, Moldenhauer G, Hammerling GJ. Kinetic analysis of peptide loading onto HLA-DR molecules mediated by HLA-DM. Proc Natl Acad Sci USA. 1996;93:9724–9.PubMed
79.
Kropshofer H, Hammerling GJ, Vogt AB. The impact of the non-classical MHC proteins HLA-DM and HLA-DO on loading of MHC class II molecules. Immunol Rev. 1999;172:267–78.PubMed
80.
Sloan VS, Cameron P, Porter G, Gammon M, Amaya M, Mellins E, et al. Mediation by HLA-DM of dissociation of peptides from HLA-DR. Nature. 1995;375:802–6.PubMed
81.
Raddrizzani L, Bono E, Vogt AB, Kropshofer H, Gallazzi F, Sturniolo T, et al. Identification of destabilizing residues in HLA class II-selected bacteriophage display libraries edited by HLA-DM. Eur J Immunol. 1999;29:660–8.PubMed
82.
Chou CL, Sadegh-Nasseri S. HLA-DM recognizes the flexible conformation of major histocompatibility complex class II. J Exp Med. 2000;192:1697–706.PubMed
83.
Stratikos E, Wiley DC, Stern LJ. Enhanced catalytic action of HLA-DM on the exchange of peptides lacking backbone hydrogen bonds between their N-terminal region and the MHC class II alpha-chain. J Immunol. 2004;172:1109–17.PubMed
84.
Stoll S, Delon J, Brotz TM, Germain RN. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes [see comment]. Science. 2002;296:1873–6.PubMed
85.
Miller MJ, Hejazi AS, Wei SH, Cahalan MD, Parker I. T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node. Proc Natl Acad Sci USA. 2004;101:998–1003.PubMed
86.
Shakhar G, Lindquist RL, Skokos D, Dudziak D, Huang JH, Nussenzweig MC, et al. Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo. Nat Immunol. 2005;6:707–14.PubMed
87.
Mempel T, Henrickson S, von Andrian U. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature. 2004;427:154–9.PubMed
88.
Hugues S, Fetler L, Bonifaz L, Helft J, Amblard F, Amigorena S. Distinct T cell dynamics in lymph nodes during the induction of tolerance and immunity. Nat Immunol. 2004;5:1235–42.PubMed
89.
Gunzer M, Schafer A, Borgmann S, Grabbe S, Zanker K, Brocker E, et al. Antigen presentation in extracellular matrix: interactions of T cells with dendritic cells are dynamic, short lived, and sequential. Immunity. 2000;13:323–32.PubMed
90.
Bousso P, Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat Immunol. 2003;4:579–85.PubMed
91.
Henrickson S, Mempel T, Mazo I, Liu B, Artyomov M, Zheng H, et al. T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat Immunol. 2008;9:282–91.PubMed
92.
Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7:83–92.PubMed
93.
Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med. 2006;203:505–11.PubMed
94.
Scholer A, Hugues S, Boissonnas A, Fetler L, Amigorena S. Intercellular adhesion molecule-1-dependent stable interactions between T cells and dendritic cells determine CD8+ T cell memory. Immunity. 2008;28:258–70.PubMed
95.
Mittelbrunn M, Martinez Del Hoyo G, Lopez-Bravo M, Martin-Cofreces NB, Scholer A, Hugues S, et al. Imaging of plasmacytoid dendritic cell interactions with T cells. Blood. 2009;113(1):75–84.PubMed
96.
Qi H, Cannons JL, Klauschen F, Schwartzberg PL, Germain RN. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature. 2008;455:764–9.PubMed
97.
Yarke CA, Dalheimer SL, Zhang N, Catron DM, Jenkins MK, Mueller DL. Proliferating CD4 T cells undergo immediate growth arrest upon cessation of TCR signaling in vivo. J Immunol. 2008;180:156–62.PubMed
98.
Gao F, Weaver EA, Lu Z, Li Y, Liao HX, Ma B, et al. Antigenicity and immunogenicity of a synthetic human immunodeficiency virus type 1 group m consensus envelope glycoprotein. J Virol. 2005;79:1154–63.PubMed
99.
Celli S, Lemaitre F, Bousso P. Real-time manipulation of T cell-dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4 T cell activation. Immunity. 2007;27:625–34.PubMed
100.
Richards KA, Chaves FA, Krafcik FR, Topham DJ, Lazarski CA, Sant AJ. Direct ex vivo analyses of HLA-DR1 transgenic mice reveal an exceptionally broad pattern of immunodominance in the primary HLA-DR1-restricted CD4 T-cell response to influenza virus hemagglutinin. J Virol. 2007;81:7608–19.PubMed
101.
Hamilton-Easton A, Eichelberger M. Virus-specific antigen presentation by different subsets of cells from lung and mediastinal lymph node tissues of influenza virus-infected mice. J Virol. 1995;69:6359–66.PubMed
102.
Geurtsvankessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C, et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells. J Exp Med. 2008;205:1621–34.PubMed
103.
Moyron-Quiroz J, Rangel-Moreno J, Carragher DM, Randall TD. The function of local lymphoid tissues in pulmonary immune responses. Adv Exp Med Biol. 2007;590:55–68.PubMed
104.
Baumgarth N, Brown L, Jackson D, Kelso A. Novel features of the respiratory tract T-cell response to influenza virus infection: lung T cells increase expression of gamma interferon mRNA in vivo and maintain high levels of mRNA expression for interleukin-5 (IL-5) and IL-10. J Virol. 1994;68:7575–81.PubMed
105.
Legge KL, Braciale TJ. Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection. Immunity. 2003;18:265–77.PubMed
106.
Bender A, Albert M, Reddy A, Feldman M, Sauter B, Kaplan G, et al. The distinctive features of influenza virus infection of dendritic cells. Immunobiology. 1998;198:552–67.PubMed
107.
Weiss S, Bogen B. MHC class II-restricted presentation of intracellular antigen. Cell. 1991;64:767–76.PubMed
108.
Sant AJ. Endogenous antigen presentation by MHC class II molecules. Immunol Res. 1994;13:253–67.PubMed
109.
Loss GE Jr, Elias CG, Fields PE, Ribaudo RK, McKisic M, Sant AJ. Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways. J Exp Med. 1993;178:73–85.PubMed
110.
Marks MS. Protein sorting within the MHC class II antigen-processing pathway. Immunol Res. 1998;17:141–54.PubMed
111.
Lechler R, Aichinger G, Lightstone L. The endogenous pathway of MHC class II antigen presentation. Immunol Rev. 1996;151:51–79.PubMed
112.
Kochs G, Garcia-Sastre A, Martinez-Sobrido L. Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol. 2007;81:7011–21.PubMed
113.
Neumann G, Castrucci MR, Kawaoka Y. Nuclear import and export of influenza virus nucleoprotein. J Virol. 1997;71:9690–700.PubMed
114.
Ye Q, Krug RM, Tao YJ. The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature. 2006;444:1078–82.PubMed
115.
Bullido R, Gomez-Puertas P, Albo C, Portela A. Several protein regions contribute to determine the nuclear and cytoplasmic localization of the influenza A virus nucleoprotein. J Gen Virol. 2000;81:135–42.PubMed
116.
Murayama R, Harada Y, Shibata T, Kuroda K, Hayakawa S, Shimizu K, et al. Influenza A virus non-structural protein 1 (NS1) interacts with cellular multifunctional protein nucleolin during infection. Biochem Biophys Res Commun. 2007;362:880–5.PubMed
117.
Fernandez-Sesma A. The influenza virus NS1 protein: inhibitor of innate and adaptive immunity. Infect Disord Drug Targets. 2007;7:336–43.PubMed
118.
Boulo S, Akarsu H, Ruigrok RW, Baudin F. Nuclear traffic of influenza virus proteins and ribonucleoprotein complexes. Virus Res. 2007;124:12–21.PubMed
119.
Engelhardt OG, Fodor E. Functional association between viral and cellular transcription during influenza virus infection. Rev Med Virol. 2006;16:329–45.PubMed
120.
Scholtissek C. Synthesis and function of influenza A virus glycoproteins. Behring Inst Mitt. 1991;89:46–53.PubMed
121.
Meier-Ewert H, Compans RW. Time course of synthesis and assembly of influenza virus proteins. J Virol. 1974;14:1083–91.PubMed
122.
Jalanko A, Kallio A, Salminen M, Ulmanen I. Efficient synthesis of influenza virus hemagglutinin in mammalian cells with an extrachromosomal Epstein-Barr virus vector. Gene. 1989;78:287–96.PubMed
123.
Alfonso C, Han JO, Williams GS, Karlsson L. The impact of H2-DM on humoral immune responses. J Immunol. 2001;167:6348–55.PubMed
124.
Swain SL, Hu H, Huston G. Class II-independent generation of CD4 memory T cells from effectors. Science. 1999;286:1381–3.PubMed
125.
Seddon B, Tomlinson P, Zamoyska R. Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells. Nat Immunol. 2003;4:680–6.PubMed
126.
Purton JF, Tan JT, Rubinstein MP, Kim DM, Sprent J, Surh CD. Antiviral CD4+ memory T cells are IL-15 dependent. J Exp Med. 2007;204:951–61.PubMed
127.
Kassiotis G, Garcia S, Simpson E, Stockinger B. Impairment of immunological memory in the absence of MHC despite survival of memory T cells. Nat Immunol. 2002;3:244–50.PubMed
128.
Catron DM, Rusch LK, Hataye J, Itano AA, Jenkins MK. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells. J Exp Med. 2006;203:1045–54.PubMed
129.
Kassiotis G, Gray D, Kiafard Z, Zwirner J, Stockinger B. Functional specialization of memory Th cells revealed by expression of integrin CD49b. J Immunol. 2006;177:968–75.PubMed
130.
Godebu E, Summers-Torres D, Lin MM, Baaten BJ, Bradley LM. Polyclonal adaptive regulatory CD4 cells that can reverse type I diabetes become oligoclonal long-term protective memory cells. J Immunol. 2008;181:1798–805.PubMed
131.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–12.PubMed
132.
Fazilleau N, Eisenbraun MD, Malherbe L, Ebright JN, Pogue-Caley RR, McHeyzer-Williams LJ, et al. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat Immunol. 2007;8:753–61.PubMed
133.
Peters B, Sette A. Integrating epitope data into the emerging web of biomedical knowledge resources. Nat Rev Immunol. 2007;7:485–90.PubMed
134.
Sette A, Peters B. Immune epitope mapping in the post-genomic era: lessons for vaccine development. Curr Opin Immunol. 2007;19:106–10.PubMed
135.
Davies MN, Flower DR. Harnessing bioinformatics to discover new vaccines. Drug Discov Today. 2007;12:389–95.PubMed
136.
Sundaresh S, Randall A, Unal B, Petersen JM, Belisle JT, Hartley MG, et al. From protein microarrays to diagnostic antigen discovery: a study of the pathogen Francisella tularensis. Bioinformatics. 2007;23:i508–18.PubMed
137.
Sette A, Newman M, Livingston B, McKinney D, Sidney J, Ishioka G, et al. Optimizing vaccine design for cellular processing, MHC binding and TCR recognition. Tissue Antigens. 2002;59:443–51.PubMed
138.
Sette A, Keogh E, Ishioka G, Sidney J, Tangri S, Livingston B, et al. Epitope identification and vaccine design for cancer immunotherapy. Curr Opin Investig Drugs. 2002;3:132–9.PubMed
139.
Terajima M, Cruz J, Raines G, Kilpatrick ED, Kennedy JS, Rothman AL, et al. Quantitation of CD8+ T cell responses to newly identified HLA-A*0201-restricted T cell epitopes conserved among vaccinia and variola (smallpox) viruses. J Exp Med. 2003;197:927–32.PubMed
140.
Wahl A, Weidanz J, Hildebrand W. Direct class I HLA antigen discovery to distinguish virus-infected and cancerous cells. Expert Rev Proteomics. 2006;3:641–52.PubMed
141.
Sette A, Fikes J. Epitope-based vaccines: an update on epitope identification, vaccine design and delivery. Curr Opin Immunol. 2003;15:461–70.PubMed
142.
Qin H, Zhou C, Wang D, Ma W, Liang X, Lin C, et al. Specific antitumor immune response induced by a novel DNA vaccine composed of multiple CTL and T helper cell epitopes of prostate cancer associated antigens. Immunol Lett. 2005;99:85–93.PubMed
143.
Chen L, Gao T, Yang N, Huang J, Chen Y, Gao T, et al. Immunization with a synthetic multiepitope antigen induces humoral and cellular immune responses to hepatitis C virus in mice. Viral Immunol. 2007;20:170–9.PubMed
144.
Fournillier A, Dupeyrot P, Martin P, Parroche P, Pajot A, Chatel L, et al. Primary and memory T cell responses induced by hepatitis C virus multiepitope long peptides. Vaccine. 2006;24:3153–64.PubMed
145.
Vuola JM, Keating S, Webster DP, Berthoud T, Dunachie S, Gilbert SC, et al. Differential immunogenicity of various heterologous prime-boost vaccine regimens using DNA and viral vectors in healthy volunteers. J Immunol. 2005;174:449–55.PubMed
146.
Kanto T, Hayashi N. Immunopathogenesis of hepatitis C virus infection: multifaceted strategies subverting innate and adaptive immunity. Intern Med. 2006;45:183–91.PubMed
147.
Fremont DH, Hendrickson WA, Marrack P, Kappler J. Structures of an MHC class II molecule with covalently bound single peptides. Science. 1996;272:1001–4.PubMed
148.
Davies MN, Flower DR. Static energy analysis of MHC class I and class II peptide-binding affinity. Methods Mol Biol. 2007;409:309–20.PubMed
149.
Zhu Y, Rudensky AY, Corper AL, Teyton L, Wilson IA. Crystal structure of MHC class II I-Ab in complex with a human CLIP peptide: prediction of an I-Ab peptide-binding motif. J Mol Biol. 2003;326:1157–74.PubMed
150.
Kumar N, Mohanty D. MODPROPEP: a program for knowledge-based modeling of protein-peptide complexes. Nucleic Acids Res. 2007;35:W549–55.PubMed
151.
Zhang W, Liu J, Niu YQ, Wang L, Hu X. A Bayesian regression approach to the prediction of MHC-II binding affinity. Comput Methods Programs Biomed. 2008;92:1–7.PubMed
152.
Calvo-Calle JM, Strug I, Nastke MD, Baker SP, Stern LJ. Human CD4+ T cell epitopes from vaccinia virus induced by vaccination or infection. PLoS Pathog. 2007;3:1511–29.PubMed
153.
Sette A, Sidney J, del Guercio MF, Southwood S, Ruppert J, Dahlberg C, et al. Peptide binding to the most frequent HLA-A class I alleles measured by quantitative molecular binding assays. Mol Immunol. 1994;31:813–22.PubMed
154.
Nielsen M, Lundegaard C, Blicher T, Peters B, Sette A, Justesen S, et al. Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan. PLoS Comput Biol. 2008;4:e1000107.PubMed
Metadata
Title
Understanding the focused CD4 T cell response to antigen and pathogenic organisms
Authors
Jason M. Weaver
Andrea J. Sant
Publication date
01-12-2009
Publisher
Humana Press Inc
Published in
Immunologic Research / Issue 2-3/2009
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-009-8095-8

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