Helper T Cell Responses to Respiratory Viruses in the Lung: Development, Virus Suppression, and Pathogenesis

Viral Immunology

Volumn 30, Issue 6, 2017, Pages 421-430

  Miyauchi, Kosuke ^a  

^a Institute of Physical and Chemical Research   (Japan)

Author keywords

helper T cell; lung pathogenesis; respiratory viruses

Indexed keywords

IMMUNOGLOBULIN G2; VIRUS VACCINE;

ADAPTIVE IMMUNITY; ARTICLE; CORONAVIRIDAE; CORONAVIRUS INFECTION; CYTOKINE PRODUCTION; CYTOTOXIC T LYMPHOCYTE; HELPER CELL; HUMAN RESPIRATORY SYNCYTIAL VIRUS; HUMORAL IMMUNITY; INFLUENZA; INFLUENZA VIRUS; INNATE IMMUNITY; LUNG ALVEOLUS MACROPHAGE; LUNG EPITHELIUM; NONHUMAN; RESPIRATORY SYNCYTIAL VIRUS INFECTION; RESPIRATORY VIRUS; RHINOVIRUS; RHINOVIRUS INFECTION; TH1 CELL; TH2 CELL; VIRAL RESPIRATORY TRACT INFECTION; VIRUS PATHOGENESIS; VIRUS REPLICATION; VIRUS VIRULENCE; HUMAN; IMMUNOLOGY; LUNG; ORTHOMYXOVIRIDAE; PATHOLOGY; PNEUMOVIRUS; RESPIRATORY TRACT INFECTION;

HUMANS; LUNG; ORTHOMYXOVIRIDAE; RESPIRATORY SYNCYTIAL VIRUSES; RESPIRATORY TRACT INFECTIONS; RHINOVIRUS; T-LYMPHOCYTES, HELPER-INDUCER;

EID: 85023739436     PISSN: 08828245     EISSN: 15578976     Source Type: Journal    
DOI: 10.1089/vim.2017.0018     Document Type: Article

References (140)

1. Adachi Y, Onodera T, Yamada Y, et al. Distinct germinal center selection at local sites shapes memory B cell response to viral escape. J Exp Med 2015;212:1709-1723.
2. Allakhverdi Z, Comeau MR, Jessup HK, et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med 2007;204:253-258.
3. Ballesteros-Tato A, Leon B, Graf BA, et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 2012;36:847-856.
4. Ballesteros-Tato A, Randall TD, Lund FE, et al. T follicular helper cell plasticity shapes pathogenic T helper 2 cell-mediated immunity to inhaled house dust mite. Immunity 2016;44:259-273.
5. Baumgarth N, Brown L, Jackson D, et al. 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;68:7575-7581.
6. Beale J, Jayaraman A, Jackson DJ, et al. Rhinovirusinduced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. Sci Transl Med 2014;6:256ra134.
7. Bedoya F, Cheng GS, Leibow A, et al. Viral antigen induces differentiation of Foxp3+ natural regulatory T cells in influenza virus-infected mice. J Immunol 2013;190: 6115-6125.
8. Bera MM, Lu B, Martin TR, et al. Th17 cytokines are critical for respiratory syncytial virus-associated airway hyperreponsiveness through regulation by complement C3a and tachykinins. J Immunol 2011;187:4245-4255.
9. Bettelli E, Korn T, and Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 2007;19:652-657.
10. Betts RJ, Prabhu N, Ho AW, et al. Influenza A virus infection results in a robust, antigen-responsive, and widely disseminated Foxp3+ regulatory T cell response. J Virol 2012;86:2817-2825.
11. Boyden AW, Legge KL, and Waldschmidt TJ. Pulmonary infection with influenza A virus induces site-specific germinal center and T follicular helper cell responses. PLoS One 2012;7:e40733.
12. Brien JD, Uhrlaub JL, and Nikolich-Zugich J. West Nile virus-specific CD4 T cells exhibit direct antiviral cytokine secretion and cytotoxicity and are sufficient for antiviral protection. J Immunol 2008;181:8568-8575.
13. Brincks EL, Roberts AD, Cookenham T, et al. Antigenspecific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection. J Immunol 2013;190:3438-3446.
14. Brown DM, Dilzer AM, Meents DL, et al. CD4 T cellmediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol 2006;177:2888-2898.
15. Brown DM, Kamperschroer C, Dilzer AM, et al. IL-2 and antigen dose differentially regulate perforin-and FasLmediated cytolytic activity in antigen specific CD4+ T cells. Cell Immunol 2009;257:69-79.
16. Brown DM, Roman E, and Swain SL. CD4 T cell responses to influenza infection. Semin Immunol 2004;16: 171-177.
17. Bueno SM, Gonzalez PA, Cautivo KM, et al. Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG. Proc Natl Acad Sci U S A 2008;105:20822-20827.
18. Bystrom J, Al-Adhoubi N, Al-Bogami M, et al. Th17 lymphocytes in respiratory syncytial virus infection. Viruses 2013;5:777-791.
19. Cannon MJ, Openshaw PJ, and Askonas BA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med 1988; 168:1163-1168.
20. Carding SR, Allan W, McMickle A, et al. Activation of cytokine genes in T cells during primary and secondary murine influenza pneumonia. J ExpMed 1993;177:475-482.
21. Casazza JP, Betts MR, Price DA, et al. Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J Exp Med 2006; 203:2865-2877.
22. Cautivo KM, Bueno SM, Cortes CM, et al. Efficient lung recruitment of respiratory syncytial virus-specific Th1 cells induced by recombinant bacillus Calmette-Guerin promotes virus clearance and protects from infection. J Immunol 2010;185:7633-7645.
23. Chang YJ, Kim HY, Albacker LA, et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 2011; 12:631-638.
24. Channappanavar R, Zhao J, and Perlman S. T cellmediated immune response to respiratory coronaviruses. Immunol Res 2014;59:118-128.
25. Christiaansen AF, Syed MA, Ten Eyck PP, et al. Altered Treg and cytokine responses in RSV-infected infants. Pediatr Res 2016;80:702-709.
26. Connors M, Giese NA, Kulkarni AB, et al. Enhanced pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSVimmunized BALB/c mice is abrogated by depletion of interleukin-4 (IL-4) and IL-10. J Virol 1994;68:5321-5325.
27. Crotta S, Davidson S, Mahlakoiv T, et al. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. PLoS Pathog 2013;9:e1003773.
28. Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014;41:529-542.
29. Crowe CR, Chen K, Pociask DA, et al. Critical role of IL-17RA in immunopathology of influenza infection. J Immunol 2009;183:5301-5310.
30. de Graaff PM, de Jong EC, van Capel TM, et al. Respiratory syncytial virus infection of monocyte-derived dendritic cells decreases their capacity to activate CD4 T cells. J Immunol 2005;175:5904-5911.
31. Durai V, and Murphy KM. Functions of murine dendritic cells. Immunity 2016;45:719-736.
32. Durant LR, Makris S, Voorburg CM, et al. Regulatory T cells prevent Th2 immune responses and pulmonary eosinophilia during respiratory syncytial virus infection in mice. J Virol 2013;87:10946-10954.
33. Eddahri F, Denanglaire S, Bureau F, et al. Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood 2009;113:2426-2433.
34. Erickson S, Matikainen S, Thyrell L, et al. Interferonalpha inhibits Stat5 DNA-binding in IL-2 stimulated primary T-lymphocytes. Eur J Biochem 2002;269:29-37.
35. Fahy JV. Type 2 inflammation in asthma-present in most, absent in many. Nat Rev Immunol 2015;15:57-65.
36. Feighery C, and Stastny P. HLA-D region-associated determinants serve as targets for human cell-mediated lysis. J Exp Med 1979;149:485-494.
37. Fukuyama S, Hiroi T, Yokota Y, et al. Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR, and NIK signaling pathways but requires the Id2 gene and CD3(-)CD4(+)CD45(+) cells. Immunity 2002;17:31-40.
38. Fulton RB, Meyerholz DK, and Varga SM. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J Immunol 2010;185:2382-2392.
39. Gallagher KM, Lauder S, Rees IW, et al. Type I interferon (IFN alpha) acts directly on human memory CD4+ T cells altering their response to antigen. J Immunol 2009;183: 2915-2920.
40. Gauduin MC, Yu Y, Barabasz A, et al. Induction of a virus-specific effector-memory CD4+ T cell response by attenuated SIV infection. J Exp Med 2006;203:2661-2672.
41. Geha RS, Jabara HH, and Brodeur SR. The regulation of immunoglobulin E class-switch recombination. Nat Rev Immunol 2003;3:721-732.
42. Gern JE, and Busse WW. Association of rhinovirus infections with asthma. Clin Microbiol Rev 1999;12:9-18.
43. Goritzka M, Makris S, Kausar F, et al. Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J Exp Med 2015;212:699-714.
44. Graham BS, Bunton LA, Wright PF, et al. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest 1991;88:1026-1033.
45. Groom JR, and Luster AD. CXCR3 in T cell function. Exp Cell Res 2011;317:620-631.
46. Halim TY, Steer CA, Matha L, et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 2014;40:425-435.
47. Harmsen A, Kusser K, Hartson L, et al. Cutting edge: organogenesis of nasal-associated lymphoid tissue (NALT) occurs independently of lymphotoxin-alpha (LT alpha) and retinoic acid receptor-related orphan receptorgamma, but the organization of NALT is LT alpha dependent. J Immunol 2002;168:986-990.
48. Hartmann BM, Li W, Jia J, et al. Mouse dendritic cell (DC) influenza virus infectivity is much lower than that for human DCs and is hemagglutinin subtype dependent. J Virol 2013;87:1916-1918.
49. Hartwig SM, Holman KM, and Varga SM. Depletion of alveolar macrophages ameliorates virus-induced disease following a pulmonary coronavirus infection. PLoS One 2014;9:e90720.
50. Hashimoto Y, Moki T, Takizawa T, et al. Evidence for phagocytosis of influenza virus-infected, apoptotic cells by neutrophils and macrophages in mice. J Immunol 2007; 178:2448-2457.
51. Havenar-Daughton C, Kolumam GA, and Murali-Krishna K. Cutting Edge: the direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection. J Immunol 2006; 176:3315-3319.
52. Haynes NM, Allen CD, Lesley R, et al. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal centerassociated subpopulation. J Immunol 2007;179:5099-5108.
53. Hellings P, Jorissen M, and Ceuppens JL. The Waldeyer's ring. Acta Otorhinolaryngol Belg 2000;54:237-241.
54. Hirahara K, Poholek A, Vahedi G, et al. Mechanisms underlying helper T-cell plasticity: implications for immune-mediated disease. J Allergy Clin Immunol 2013; 131:1276-1287.
55. Iwasaki A, and Pillai PS. Innate immunity to influenza virus infection. Nat Rev Immunol 2014;14:315-328.
56. Iwata M, and Sato A. Morphological and immunohistochemical studies of the lungs and bronchus-associated lymphoid tissue in a rat model of chronic pulmonary infection with Pseudomonas aeruginosa. Infect Immun 1991; 59:1514-1520.
57. Jackson DJ, Makrinioti H, Rana BM, et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J Respir Crit Care Med 2014;190:1373-1382.
58. Jang S, Morris S, and Lukacs NW. TSLP promotes induction of Th2 differentiation but is not necessary during established allergen-induced pulmonary disease. PLoS One 2013;8:e56433.
59. Jarjour NN, and Esnault S. Interleukin-33: a potential link between rhinovirus infections and asthma exacerbation. Am J Respir Crit Care Med 2014;190:1336-1337.
60. Jellison ER, Kim SK, and Welsh RM. Cutting edge: MHC class II-restricted killing in vivo during viral infection. J Immunol 2005;174:614-618.
61. Jewell NA, Cline T, Mertz SE, et al. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J Virol 2010;84:11515-11522.
62. Kaiko GE, Loh Z, Spann K, et al. Toll-like receptor 7 gene deficiency and early-life Pneumovirus infection interact to predispose toward the development of asthmalike pathology in mice. J Allergy Clin Immunol 2013;131: 1331-1339 e1310.
63. Kallal LE, Hartigan AJ, Hogaboam CM, et al. Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology. J Immunol 2010;185:4137-4147.
64. Kato A, Favoreto S, Jr., Avila PC, et al. TLR3-and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J Immunol 2007;179:1080-1087.
65. Kim TH, and Lee HK. Differential roles of lung dendritic cell subsets against respiratory virus infection. Immune Netw 2014;14:128-137.
66. Krammer F, and Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov 2015; 14:167-182.
67. Krishnamoorthy N, Khare A, Oriss TB, et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat Med 2012;18:1525-1530.
68. Kudva A, Scheller EV, Robinson KM, et al. Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice. J Immunol 2011;186:1666-1674.
69. Lee DC, Harker JA, Tregoning JS, et al. CD25+ natural regulatory T cells are critical in limiting innate and adaptive immunity and resolving disease following respiratory syncytial virus infection. J Virol 2010;84:8790-8798.
70. Legg JP, Hussain IR, Warner JA, et al. Type 1 and type 2 cytokine imbalance in acute respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med 2003;168: 633-639.
71. Leon B, Bradley JE, Lund FE, et al. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun 2014;5:3495.
72. Li L, Xia Y, Nguyen A, et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J Immunol 1999;162:2477-2487.
73. Li T, Qiu Z, Zhang L, et al. Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J Infect Dis 2004;189:648-651.
74. Lin Y, Wang W, Jin H, et al. Comparison of murine thymic stromal lymphopoietin-and polyinosinic polycytidylic acid-mediated placental dendritic cell activation. J Reprod Immunol 2009;79:119-128.
75. Locksley RM, and Fahy JV. Asthma and the flu: a tricky two-step. Immunol Cell Biol 2014;92:389-391.
76. Loebbermann J, Schnoeller C, Thornton H, et al. IL-10 regulates viral lung immunopathology during acute respiratory syncytial virus infection in mice. PLoS One 2012;7:e32371.
77. Lukacher AE, Morrison LA, Braciale VL, et al. Expression of specific cytolytic activity by H-2I region-restricted, influenza virus-specific T lymphocyte clones. J Exp Med 1985;162:171-187.
78. Lukacs NW, Moore ML, Rudd BD, et al. Differential immune responses and pulmonary pathophysiology are induced by two different strains of respiratory syncytial virus. Am J Pathol 2006;169:977-986.
79. Lund FE, Partida-Sanchez S, Lee BO, et al. Lymphotoxinalpha-deficient mice make delayed, but effective, T and B cell responses to influenza. J Immunol 2002;169:5236-5243.
80. Luthje K, Kallies A, Shimohakamada Y, et al. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat Immunol 2012;13:491-498.
81. Maimone MM, Morrison LA, Braciale VL, et al. Features of target cell lysis by class I and class II MHC-restricted cytolytic T lymphocytes. J Immunol 1986;137:3639-3643.
82. Marone G, Triggiani M, and de Paulis A. Mast cells and basophils: friends as well as foes in bronchial asthma Trends Immunol 2005;26:25-31.
83. Maroof A, Yorgensen YM, Li Y, et al. Intranasal vaccination promotes detrimental Th17-mediated immunity against influenza infection. PLoS Pathog 2014;10: e1003875.
84. McKinstry KK, Strutt TM, Buck A, et al. IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high-dose challenge. J Immunol 2009;182:7353-7363.
85. Mehta AK, Duan W, Doerner AM, et al. Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. J Allergy Clin Immunol 2016;137:278-288 e276.
86. Miyauchi K, Sugimoto-Ishige A, Harada Y, et al. Protective neutralizing influenza antibody response in the absence of T follicular helper cells. Nat Immunol 2016;17: 1447-1458.
87. Mordstein M, Neugebauer E, Ditt V, et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol 2010;84:5670-5677.
88. Moyron-Quiroz JE, Rangel-Moreno J, Kusser K, et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 2004;10:927-934.
89. Munir S, Hillyer P, Le Nouen C, et al. Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. PLoS Pathog 2011;7:e1001336.
90. Murphy TL, Grajales-Reyes GE, Wu X, et al. Transcriptional control of dendritic cell development. Annu Rev Immunol 2016;34:93-119.
91. Neyt K, and Lambrecht BN. The role of lung dendritic cell subsets in immunity to respiratory viruses. Immunol Rev 2013;255:57-67.
92. Nurieva RI, Chung Y, Hwang D, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 2008;29:138-149.
93. Nurieva RI, Chung Y, Martinez GJ, et al. Bcl6 mediates the development of T follicular helper cells. Science 2009; 325:1001-1005.
94. Odendall C, and Kagan JC. The unique regulation and functions of type III interferons in antiviral immunity. Curr Opin Virol 2015;12:47-52.
95. Oh S, and Eichelberger MC. Polarization of allogeneic Tcell responses by influenza virus-infected dendritic cells. J Virol 2000;74:7738-7744.
96. Ohkura N, Kitagawa Y, and Sakaguchi S. Development and maintenance of regulatory T cells. Immunity 2013;38: 414-423.
97. Okada T, Moriyama S, and Kitano M. Differentiation of germinal center B cells and follicular helper T cells as viewed by tracking Bcl6 expression dynamics. Immunol Rev 2012;247:120-132.
98. Oliphant S, Lines JL, Hollifield ML, et al. Regulatory T cells are critical for clearing influenza A virus in neonatal mice. Viral Immunol 2015;28:580-589.
99. Onodera T, Takahashi Y, Yokoi Y, et al. Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection. Proc Natl Acad Sci U S A 2012;109:2485-2490.
100. Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol 2012;12:821-832.
101. Pletneva LM, Haller O, Porter DD, et al. Induction of type I interferons and interferon-inducible Mx genes during respiratory syncytial virus infection and reinfection in cotton rats. J Gen Virol 2008;89:261-270.
102. Raju R, Peters BS, and Breen RA. Lung infections in the HIV-infected adult. Curr Opin Pulm Med 2012;18:253-258.
103. Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M, et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol 2011;12:639-646.
104. Rangel-Moreno J, Moyron-Quiroz JE, Hartson L, et al. Pulmonary expression of CXC chemokine ligand 13, CC chemokine ligand 19, and CC chemokine ligand 21 is essential for local immunity to influenza. Proc Natl Acad Sci U S A 2007;104:10577-10582.
105. Riese RJ, Finn PW, and Shapiro SD. Influenza and asthma: adding to the respiratory burden. Nat Immunol 2004; 5:243-244.
106. Saito T, Kitayama D, Sakamoto A, et al. Effective collaboration between IL-4 and IL-21 on B cell activation. Immunobiology 2008;213:545-555.
107. Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell 2008;133:775-787.
108. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev 2001;14:778-809, table of contents.
109. Schenkel JM, Fraser KA, Beura LK, et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 2014;346:98-101.
110. Schmidt A, Oberle N, and Krammer PH. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol 2012;3:51.
111. Silas S, Fitzsimmons CM, Jones FM, et al. Human IgE responses to different splice variants of Schistosoma mansoni tropomyosin: associations with immunity. Int J Parasitol 2014;44:381-390.
112. Sims AC, Baric RS, Yount B, et al. Severe acute respiratory syndrome coronavirus infection of human ciliated airway epithelia: role of ciliated cells in viral spread in the conducting airways of the lungs. J Virol 2005;79:15511-15524.
113. Smed-Sorensen A, Chalouni C, Chatterjee B, et al. Influenza A virus infection of human primary dendritic cells impairs their ability to cross-present antigen to CD8 T cells. PLoS Pathog 2012;8:e1002572.
114. Snapper CM, and Paul WE. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 1987;236:944-947.
115. Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673-680.
116. Spann KM, Tran KC, Chi B, et al. Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages [corrected]. J Virol 2004;78:4363-4369.
117. Stokes KL, Chi MH, Sakamoto K, et al. Differential pathogenesis of respiratory syncytial virus clinical isolates in BALB/c mice. J Virol 2011;85:5782-5793.
118. Suess T, Remschmidt C, Schink SB, et al. Comparison of shedding characteristics of seasonal influenza virus (sub)types and influenza A(H1N1)pdm09; Germany, 2007-2011. PLoS One 2012;7:e51653.
119. Suto A, Wurster AL, Reiner SL, et al. IL-21 inhibits IFNgamma production in developing Th1 cells through the repression of Eomesodermin expression. J Immunol 2006; 177:3721-3727.
120. Swain SL, McKinstry KK, and Strutt TM. Expanding roles for CD4(+) T cells in immunity to viruses. Nat Rev Immunol 2012;12:136-148.
121. Takeuchi A, Badr Mel S, Miyauchi K, et al. CRTAM determines the CD4+ cytotoxic T lymphocyte lineage. J Exp Med 2016;213:123-138.
122. Tekkanat KK, Maassab HF, Cho DS, et al. IL-13-induced airway hyperreactivity during respiratory syncytial virus infection is STAT6 dependent. J Immunol 2001;166: 3542-3548.
123. Tisoncik JR, Korth MJ, Simmons CP, et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012;76: 16-32.
124. Tough DF, Borrow P, and Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 1996;272:1947-1950.
125. Ulmer JB, Fu TM, Deck RR, et al. Protective CD4+ and CD8+ T cells against influenza virus induced by vaccination with nucleoprotein DNA. J Virol 1998;72:5648-5653.
126. Vogelzang A, McGuire HM, Yu D, et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 2008;29:127-137.
127. Wagner H, Starzinski-Powitz A, Jung H, et al. Induction of I region-restricted hapten-specific cytotoxic T lymphocytes. J Immunol 1977;119:1365-1368.
128. Weiss KA, Christiaansen AF, Fulton RB, et al. Multiple CD4+ T cell subsets produce immunomodulatory IL-10 during respiratory syncytial virus infection. J Immunol 2011;187:3145-3154.
129. Wesa AK, and Galy A. IL-1 beta induces dendritic cells to produce IL-12. Int Immunol 2001;13:1053-1061.
130. Wohlleben G, Muller J, Tatsch U, et al. Influenza A virus infection inhibits the efficient recruitment of Th2 cells into the airways and the development of airway eosinophilia. J Immunol 2003;170:4601-4611.
131. Wong RS, Wu A, To KF, et al. Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis. BMJ 2003;326:1358-1362.
132. Woodland DL, and Kohlmeier JE. Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol 2009;9:153-161.
133. Wu P, and Hartert TV. Evidence for a causal relationship between respiratory syncytial virus infection and asthma. Expert Rev Anti Infect Ther 2011;9:731-745.
134. Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol 2015;15:271-282.
135. Yoshikawa T, Hill T, Li K, et al. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol 2009;83:3039-3048.
136. You D, Marr N, Saravia J, et al. IL-4Ralpha on CD4+ T cells plays a pathogenic role in respiratory syncytial virus reinfection in mice infected initially as neonates. J Leukoc Biol 2013;93:933-942.
137. Yu D, Rao S, Tsai LM, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009;31:457-468.
138. Zhao J, Zhao J, Van Rooijen N, et al. Evasion by stealth: inefficient immune activation underlies poor T cell response and severe disease in SARS-CoV-infected mice. PLoS Pathog 2009;5:e1000636.
139. Zhu J, Yamane H, and Paul WE. Differentiation of effector CD4 T cell populations (∗). Annu Rev Immunol 2010;28:445-489.
140. Zotos D, Coquet JM, Zhang Y, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med 2010; 207:365-378.