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Influenza Pathogenesis and Control - Volume II pp 423–455Cite as

The Effector T Cell Response to Influenza Infection

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 386))

Abstract

Influenza virus infection induces a potent initial innate immune response, which serves to limit the extent of viral replication and virus spread. However, efficient (and eventual) viral clearance within the respiratory tract requires the subsequent activation, rapid proliferation, recruitment, and expression of effector activities by the adaptive immune system, consisting of antibody producing B cells and influenza-specific T lymphocytes with diverse functions. The ensuing effector activities of these T lymphocytes ultimately determine (along with antibodies) the capacity of the host to eliminate the viruses and the extent of tissue damage. In this review, we describe this effector T cell response to influenza virus infection. Based on information largely obtained in experimental settings (i.e., murine models), we will illustrate the factors regulating the induction of adaptive immune T cell responses to influenza, the effector activities displayed by these activated T cells, the mechanisms underlying the expression of these effector mechanisms, and the control of the activation/differentiation of these T cells, in situ, in the infected lungs.

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Abbreviations

APC:

Antigen presenting cell

Bid:

BH3 interacting-domain death agonist

Blimp-1:

B lymphocyte–induced maturation protein-1

cRDC:

Conventional RDC

CTL:

Cytotoxic T lymphocyte

DAMP:

Damage-associated molecular pattern

DC:

Dendritic cell

DLN:

Draining lymph node

FADD:

Fas-associated death domain (FADD)

FasL:

Fas ligand

IAV:

Influenza A virus

IFN:

Interferon

IL:

Interleukin

IRF:

IFN Regulatory factor

MIP-1α:

Macrophage inflammatory protein-1α

MARCO:

Macrophage receptor with collagenous structure

MAVS:

Mitochondrial antiviral signaling

MHC:

Major histocompatibility complex

Mo-RDC:

Monocyte-like RDC

NLR:

NOD-like receptor

PAMP:

Pathogen-associated molecular pattern

pDC:

Plasmacytoid DC

PRR:

Pattern recognition receptor

RDC:

Respiratory DC

REC:

Respiratory epithelial cell

RIG-I:

Retnoic acid-inducible gene 1

RLR:

Rig-I-like receptor

TCR:

T cell receptor

TH :

T helper

TipDC:

TNF+iNOS+ DC

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

TRAIL-DR:

TRAIL-death receptor

References

  • Aldridge JR Jr, Moseley CE, Boltz DA, Negovetich NJ, Reynolds C, Franks J, Brown SA, Doherty PC, Webster RG, Thomas PG (2009) TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc Natl Acad Sci USA 106:5306–5311

    CAS  PubMed Central  PubMed  Google Scholar 

  • Allavena P, Giardina G, Bianchi G, Mantovani A (1997) IL-15 is chemotactic for natural killer cells and stimulates their adhesion to vascular endothelium. J Leukoc Biol 61:729–735

    CAS  PubMed  Google Scholar 

  • Allen S, Turner SJ, Bourges D, Gleeson PA, van Driel IR (2011) Shaping the T-cell repertoire in the periphery. Immunol Cell Biol 89:60–69

    PubMed  Google Scholar 

  • Anderson KG, Sung H, Skon CN, Lefrancois L, Deisinger A, Vezys V, Masopust D (2012) Cutting edge: intravascular staining redefines lung CD8 T cell responses. J Immunol 189:2702–2706

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE, Randall TD (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36:847–856

    CAS  PubMed Central  PubMed  Google Scholar 

  • Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    CAS  PubMed  Google Scholar 

  • Baumgarth N, Kelso A (1996) In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue. J Virol 70:4411–4418

    CAS  PubMed Central  PubMed  Google Scholar 

  • Belisle SE, Tisoncik JR, Korth MJ, Carter VS, Proll SC, Swayne DE, Pantin-Jackwood M, Tumpey TM, Katze MG (2010) Genomic profiling of tumor necrosis factor alpha (TNF-alpha) receptor and interleukin-1 receptor knockout mice reveals a link between TNF-alpha signaling and increased severity of 1918 pandemic influenza virus infection. J Virol 84:12576–12588

    CAS  PubMed Central  PubMed  Google Scholar 

  • Belz GT, Smith CM, Kleinert L, Reading P, Brooks A, Shortman K, Carbone FR, Heath WR (2004) Distinct migrating and nonmigrating dendritic cell populations are involved in MHC class I-restricted antigen presentation after lung infection with virus. Proc Natl Acad Sci USA 101:8670–8675

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bender BS, Croghan T, Zhang L, Small PA Jr (1992) Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge. J Exp Med 175:1143–1145

    CAS  PubMed  Google Scholar 

  • Benedict CA, Ware CF (2012) TRAIL: not just for tumors anymore? J Exp Med 209:1903–1906

    CAS  PubMed Central  PubMed  Google Scholar 

  • Blumenthal R, Millard PJ, Henkart MP, Reynolds CW, Henkart PA (1984) Liposomes as targets for granule cytolysin from cytotoxic large granular lymphocyte tumors. Proc Natl Acad Sci USA 81:5551–5555

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bot A, Bot S, Bona CA (1998) Protective role of gamma interferon during the recall response to influenza virus. J Virol 72:6637–6645

    CAS  PubMed Central  PubMed  Google Scholar 

  • Braciale TJ, Sun J, Kim TS (2012) Regulating the adaptive immune response to respiratory virus infection. Nat Rev Immunol 12:295–305

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brincks EL, Katewa A, Kucaba TA, Griffith TS, Legge KL (2008) CD8 T cells utilize TRAIL to control influenza virus infection. J Immunol 181:4918–4925

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brincks EL, Gurung P, Langlois RA, Hemann EA, Legge KL, Griffith TS (2011) The magnitude of the T cell response to a clinically significant dose of influenza virus is regulated by TRAIL. J Immunol 187:4581–4588

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brown DM, Dilzer AM, Meents DL, Swain SL (2006) CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol 177:2888–2898

    CAS  PubMed  Google Scholar 

  • Brown DM, Lee S, Garcia-Hernandez Mde L, Swain SL (2012) Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol 86:6792–6803

    CAS  PubMed Central  PubMed  Google Scholar 

  • Buzza MS, Zamurs L, Sun J, Bird CH, Smith AI, Trapani JA, Froelich CJ, Nice EC, Bird PI (2005) Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin. J Biol Chem 280:23549–23558

    CAS  PubMed  Google Scholar 

  • Cook DN, Beck MA, Coffman TM, Kirby SL, Sheridan JF, Pragnell IB, Smithies O (1995) Requirement of MIP-1 alpha for an inflammatory response to viral infection. Science 269:1583–1585

    CAS  PubMed  Google Scholar 

  • Couper KN, Blount DG, Riley EM (2008) IL-10: The master regulator of immunity to infection. J Immunol 180:5771–5777

    CAS  PubMed  Google Scholar 

  • Crotty S, Johnston RJ, Schoenberger SP (2010) Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol 11:114–120

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cullen SP, Adrain C, Luthi AU, Duriez PJ, Martin SJ (2007) Human and murine granzyme B exhibit divergent substrate preferences. J Cell Biol 176:435–444

    CAS  PubMed Central  PubMed  Google Scholar 

  • Damjanovic D, Divangahi M, Kugathasan K, Small CL, Zganiacz A, Brown EG, Hogaboam CM, Gauldie J, Xing Z (2011) Negative regulation of lung inflammation and immunopathology by TNF-alpha during acute influenza infection. Am J Pathol 179:2963–2976

    CAS  PubMed Central  PubMed  Google Scholar 

  • del Rio ML, Rodriguez-Barbosa JI, Kremmer E, Forster R (2007) CD103- and CD103+ bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4+ and CD8+ T cells. J Immunol 178:6861–6866

    PubMed  Google Scholar 

  • Desch AN, Randolph GJ, Murphy K, Gautier EL, Kedl RM, Lahoud MH, Caminschi I, Shortman K, Henson PM, Jakubzick CV (2011) CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen. J Exp Med 208:1789–1797

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dockrell DH (2003) The multiple roles of Fas ligand in the pathogenesis of infectious diseases. Clin Microbiol Infect 9:766–779

    CAS  PubMed  Google Scholar 

  • Dolfi DV, Duttagupta PA, Boesteanu AC, Mueller YM, Oliai CH, Borowski AB, Katsikis PD (2011) Dendritic cells and CD28 costimulation are required to sustain virus-specific CD8+ T cell responses during the effector phase in vivo. J Immunol 186:4599–4608

    CAS  PubMed  Google Scholar 

  • Dustin ML, Long EO (2010) Cytotoxic immunological synapses. Immunol Rev 235:24–34

    CAS  PubMed Central  PubMed  Google Scholar 

  • Edelson BT, Kc W, Juang R, Kohyama M, Benoit LA, Klekotka PA, Moon C, Albring JC, Ise W, Michael DG, Bhattacharya D, Stappenbeck TS, Holtzman MJ, Sung SS, Murphy TL, Hildner K, Murphy KM (2010) Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med 207:823–836

    CAS  PubMed Central  PubMed  Google Scholar 

  • Eichelberger M, Allan W, Zijlstra M, Jaenisch R, Doherty PC (1991) Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med 174:875–880

    CAS  PubMed  Google Scholar 

  • Faroudi M, Utzny C, Salio M, Cerundolo V, Guiraud M, Muller S, Valitutti S (2003) Lytic versus stimulatory synapse in cytotoxic T lymphocyte/target cell interaction: manifestation of a dual activation threshold. Proc Natl Acad Sci USA 100:14145–14150

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fulton RB, Varga SM (2010) Editorial: CD8 T cells cut back on calcium intake in the lungs. J Leukoc Biol 87:961–964

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fulton RB, Olson MR, Varga SM (2008) Regulation of cytokine production by virus-specific CD8 T cells in the lungs. J Virol 82:7799–7811

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gereke M, Jung S, Buer J, Bruder D (2009) Alveolar type II epithelial cells present antigen to CD4(+) T cells and induce Foxp3(+) regulatory T cells. Am J Respir Crit Care Med 179:344–355

    PubMed  Google Scholar 

  • GeurtsvanKessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C, Thielemans K, Bennett C, Clausen BE, Hoogsteden HC, Osterhaus AD, Rimmelzwaan GF, Lambrecht BN (2008) Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells. J Exp Med 205:1621–1634

    CAS  PubMed Central  PubMed  Google Scholar 

  • Graham MB, Dalton DK, Giltinan D, Braciale VL, Stewart TA, Braciale TJ (1993) Response to influenza infection in mice with a targeted disruption in the interferon gamma gene. J Exp Med 178:1725–1732

    CAS  PubMed  Google Scholar 

  • Graham MB, Braciale VL, Braciale TJ (1994) Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med 180:1273–1282

    CAS  PubMed  Google Scholar 

  • Grell M, Douni E, Wajant H, Lohden M, Clauss M, Maxeiner B, Georgopoulos S, Lesslauer W, Kollias G, Pfizenmaier K, Scheurich P (1995) The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 83:793–802

    CAS  PubMed  Google Scholar 

  • Guo Y, Chen J, Shi L, Fan Z (2010) Valosin-containing protein cleavage by granzyme K accelerates an endoplasmic reticulum stress leading to caspase-independent cytotoxicity of target tumor cells. J Immunol 185:5348–5359

    CAS  PubMed  Google Scholar 

  • Hao X, Kim TS, Braciale TJ (2008) Differential response of respiratory dendritic cell subsets to influenza virus infection. J Virol 82:4908–4919

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hargadon KM, Zhou H, Albrecht RA, Dodd HA, Garcia-Sastre A, Braciale TJ (2011) Major histocompatibility complex class II expression and hemagglutinin subtype influence the infectivity of type A influenza virus for respiratory dendritic cells. J Virol 85:11955–11963

    CAS  PubMed Central  PubMed  Google Scholar 

  • Heer AK, Shamshiev A, Donda A, Uematsu S, Akira S, Kopf M, Marsland BJ (2007) TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses. J Immunol 178:2182–2191

    CAS  PubMed  Google Scholar 

  • Helft J, Ginhoux F, Bogunovic M, Merad M (2010) Origin and functional heterogeneity of non-lymphoid tissue dendritic cells in mice. Immunol Rev 234:55–75

    CAS  PubMed  Google Scholar 

  • Helft J, Manicassamy B, Guermonprez P, Hashimoto D, Silvin A, Agudo J, Brown BD, Schmolke M, Miller JC, Leboeuf M, Murphy KM, Garcia-Sastre A, Merad M (2012) Cross-presenting CD103+ dendritic cells are protected from influenza virus infection. J Clin Invest 122:4037–4047

    CAS  PubMed Central  PubMed  Google Scholar 

  • Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Corazza N, Brunner T, Seeger W, Lohmeyer J (2008) Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand. J Exp Med 205:3065–3077

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ho AW, Prabhu N, Betts RJ, Ge MQ, Dai X, Hutchinson PE, Lew FC, Wong KL, Hanson BJ, Macary PA, Kemeny DM (2011) Lung CD103+ dendritic cells efficiently transport influenza virus to the lymph node and load viral antigen onto MHC class I for presentation to CD8 T cells. J Immunol 187:6011–6021

    CAS  PubMed  Google Scholar 

  • Hou S, Doherty PC (1995) Clearance of Sendai virus by CD8+ T cells requires direct targeting to virus-infected epithelium. Eur J Immunol 25:111–116

    CAS  PubMed  Google Scholar 

  • Hua L, Yao S, Pham D, Jiang L, Wright J, Sawant D, Dent AL, Braciale TJ, Kaplan MH, Sun J (2013) Cytokine-dependent induction of CD4+ T cells with cytotoxic potential during influenza virus infection. J Virol 87:11884–11893

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hufford MM, Kim TS, Sun J, Braciale TJ (2011) Antiviral CD8+ T cell effector activities in situ are regulated by target cell type. J Exp Med 208:167–180

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hufford MM, Richardson G, Zhou H, Manicassamy B, Garcia-Sastre A, Enelow RI, Braciale TJ (2012) Influenza-infected neutrophils within the infected lungs act as antigen presenting cells for anti-viral CD8(+) T cells. PLoS One 7:e46581

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huse M, Lillemeier BF, Kuhns MS, Chen DS, Davis MM (2006) T cells use two directionally distinct pathways for cytokine secretion. Nat Immunol 7:247–255

    CAS  PubMed  Google Scholar 

  • Hussell T, Pennycook A, Openshaw PJ (2001) Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology. Eur J Immunol 31:2566–2573

    CAS  PubMed  Google Scholar 

  • Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A (2009) Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med 206:79–87

    CAS  PubMed Central  PubMed  Google Scholar 

  • Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, Zhong G, Hanson A, Katsura H, Watanabe S, Li C, Kawakami E, Yamada S, Kiso M, Suzuki Y, Maher EA, Neumann G, Kawaoka Y (2012) Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486:420–428

    CAS  PubMed Central  PubMed  Google Scholar 

  • Isaaz S, Baetz K, Olsen K, Podack E, Griffiths GM (1995) Serial killing by cytotoxic T lymphocytes: T cell receptor triggers degranulation, re-filling of the lytic granules and secretion of lytic proteins via a non-granule pathway. Eur J Immunol 25:1071–1079

    CAS  PubMed  Google Scholar 

  • Ishikawa E, Nakazawa M, Yoshinari M, Minami M (2005) Role of tumor necrosis factor-related apoptosis-inducing ligand in immune response to influenza virus infection in mice. J Virol 79:7658–7663

    CAS  PubMed Central  PubMed  Google Scholar 

  • Joeckel LT, Wallich R, Martin P, Sanchez-Martinez D, Weber FC, Martin SF, Borner C, Pardo J, Froelich C, Simon MM (2011) Mouse granzyme K has pro-inflammatory potential. Cell Death Differ 18:1112–1119

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kagi D, Ledermann B, Burki K, Seiler P, Odermatt B, Olsen KJ, Podack ER, Zinkernagel RM, Hengartner H (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37

    CAS  PubMed  Google Scholar 

  • Kaiserman D, Bird CH, Sun J, Matthews A, Ung K, Whisstock JC, Thompson PE, Trapani JA, Bird PI (2006) The major human and mouse granzymes are structurally and functionally divergent. J Cell Biol 175:619–630

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kallies A, Xin A, Belz GT, Nutt SL (2009) Blimp-1 transcription factor is required for the differentiation of effector CD8(+) T cells and memory responses. Immunity 31:283–295

    CAS  PubMed  Google Scholar 

  • Kandasamy M, Ying PC, Ho AW, Sumatoh HR, Schlitzer A, Hughes TR, Kemeny DM, Morgan BP, Ginhoux F, Sivasankar B (2013) Complement mediated signaling on pulmonary CD103(+) dendritic cells is critical for their migratory function in response to influenza infection. PLoS Pathog 9:e1003115

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, Taraporewala ZF, Miller D, Patton JT, Inohara N, Nunez G (2006) Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem 281:36560–36568

    CAS  PubMed  Google Scholar 

  • Karpus WJ, Lukacs NW, Kennedy KJ, Smith WS, Hurst SD, Barrett TA (1997) Differential CC chemokine-induced enhancement of T helper cell cytokine production. J Immunol 158:4129–4136

    CAS  PubMed  Google Scholar 

  • Karupiah G, Chen JH, Mahalingam S, Nathan CF, MacMicking JD (1998) Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice. J Exp Med 188:1541–1546

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kayagaki N, Kawasaki A, Ebata T, Ohmoto H, Ikeda S, Inoue S, Yoshino K, Okumura K, Yagita H (1995) Metalloproteinase-mediated release of human Fas ligand. J Exp Med 182:1777–1783

    CAS  PubMed  Google Scholar 

  • Kim TS, Braciale TJ (2009) Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses. PLoS One 4:e4204

    PubMed Central  PubMed  Google Scholar 

  • Kohlmeier JE, Woodland DL (2009) Immunity to respiratory viruses. Annu Rev Immunol 27:61–82

    CAS  PubMed  Google Scholar 

  • Kotelkin A, Prikhod’ko EA, Cohen JI, Collins PL, Bukreyev A (2003) Respiratory syncytial virus infection sensitizes cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Virol 77:9156–9172

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koyama S, Ishii KJ, Kumar H, Tanimoto T, Coban C, Uematsu S, Kawai T, Akira S (2007) Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol 179:4711–4720

    CAS  PubMed  Google Scholar 

  • Kupfer A, Singer SJ, Dennert G (1986) On the mechanism of unidirectional killing in mixtures of two cytotoxic T lymphocytes. Unidirectional polarization of cytoplasmic organelles and the membrane-associated cytoskeleton in the effector cell. J Exp Med 163:489–498

    CAS  PubMed  Google Scholar 

  • Lambrecht BN, Hammad H (2012) Lung dendritic cells in respiratory viral infection and asthma: from protection to immunopathology. Annu Rev Immunol 30:243–270

    CAS  PubMed  Google Scholar 

  • Langlois RA, Legge KL (2011) Plasmacytoid dendritic cells enhance mortality during lethal influenza infections by eliminating virus-specific CD8 T cells. J Immunol 184:4440–4446

    Google Scholar 

  • Lawrence CW, Braciale TJ (2004) Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection. J Immunol 173:1209–1218

    CAS  PubMed  Google Scholar 

  • Le Goffic R, Balloy V, Lagranderie M, Alexopoulou L, Escriou N, Flavell R, Chignard M, Si-Tahar M (2006) Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog 2:e53

    PubMed Central  PubMed  Google Scholar 

  • Lee N, Wong CK, Chan PK, Chan MC, Wong RY, Lun SW, Ngai KL, Lui GC, Wong BC, Lee SK, Choi KW, Hui DS (2011) Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults. PLoS One 6:e26050

    CAS  PubMed Central  PubMed  Google Scholar 

  • Legge KL, Braciale TJ (2005) Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression. Immunity 23:649–659

    CAS  PubMed  Google Scholar 

  • Lettau M, Qian J, Linkermann A, Latreille M, Larose L, Kabelitz D, Janssen O (2006) The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse. Proc Natl Acad Sci U S A 103:5911–5916

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li JH, Rosen D, Ronen D, Behrens CK, Krammer PH, Clark WR, Berke G (1998) The regulation of CD95 ligand expression and function in CTL. J Immunol 161:3943–3949

    CAS  PubMed  Google Scholar 

  • Lin KL, Suzuki Y, Nakano H, Ramsburg E, Gunn MD (2008) CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol 180:2562–2572

    CAS  PubMed  Google Scholar 

  • Lopez JA, Brennan AJ, Whisstock JC, Voskoboinik I, Trapani JA (2012) Protecting a serial killer: pathways for perforin trafficking and self-defense ensure sequential target cell death. Trends Immunol 33:406–412

    CAS  PubMed  Google Scholar 

  • Lowin B, Mattman C, Hahne M, Tschopp J (1996) Comparison of Fas(Apo-1/CD95)- and perforin-mediated cytotoxicity in primary T lymphocytes. Int Immunol 8:57–63

    CAS  PubMed  Google Scholar 

  • Lukacher AE, Braciale VL, Braciale TJ (1984) In vivo effector function of influenza virus-specific cytotoxic T lymphocyte clones is highly specific. J Exp Med 160:814–826

    CAS  PubMed  Google Scholar 

  • Lum JJ, Pilon AA, Sanchez-Dardon J, Phenix BN, Kim JE, Mihowich J, Jamison K, Hawley-Foss N, Lynch DH, Badley AD (2001) Induction of cell death in human immunodeficiency virus-infected macrophages and resting memory CD4 T cells by TRAIL/Apo2l. J Virol 75:11128–11136

    CAS  PubMed Central  PubMed  Google Scholar 

  • Man K, Miasari M, Shi W, Xin A, Henstridge DC, Preston S, Pellegrini M, Belz GT, Smyth GK, Febbraio MA, Nutt SL, Kallies A (2013) The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat Immunol 14:1155–1165

    CAS  PubMed  Google Scholar 

  • Manicassamy B, Manicassamy S, Belicha-Villanueva A, Pisanelli G, Pulendran B, Garcia-Sastre A (2010) Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc Natl Acad Sci USA 107:11531–11536

    CAS  PubMed Central  PubMed  Google Scholar 

  • Masopust D, Schenkel JM (2013) The integration of T cell migration, differentiation and function. Nat Rev Immunol 13:309–320

    CAS  PubMed  Google Scholar 

  • Mattei F, Schiavoni G, Belardelli F, Tough DF (2001) IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol 167:1179–1187

    CAS  PubMed  Google Scholar 

  • McGill J, Legge KL (2009) Cutting edge: contribution of lung-resident T cell proliferation to the overall magnitude of the antigen-specific CD8 T cell response in the lungs following murine influenza virus infection. J Immunol 183:4177–4181

    CAS  PubMed Central  PubMed  Google Scholar 

  • McGill J, Van Rooijen N, Legge KL (2008) Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs. J Exp Med 205:1635–1646

    CAS  PubMed Central  PubMed  Google Scholar 

  • McGill J, Van Rooijen N, Legge KL (2010) IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection. J Exp Med 207:521–534

    CAS  PubMed Central  PubMed  Google Scholar 

  • McKinstry KK, Strutt TM, Buck A, Curtis JD, Dibble JP, Huston G, Tighe M, Hamada H, Sell S, Dutton RW, Swain SL (2009) IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high-dose challenge. J Immunol 182:7353–7363

    CAS  PubMed Central  PubMed  Google Scholar 

  • Menten P, Wuyts A, Van Damme J (2002) Macrophage inflammatory protein-1. Cytokine Growth Factor Rev 13:455–481

    CAS  PubMed  Google Scholar 

  • Metkar SS, Menaa C, Pardo J, Wang B, Wallich R, Freudenberg M, Kim S, Raja SM, Shi L, Simon MM, Froelich CJ (2008) Human and mouse granzyme A induce a proinflammatory cytokine response. Immunity 29:720–733

    CAS  PubMed  Google Scholar 

  • Mikhak Z, Strassner JP, Luster AD (2013) Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4. J Exp Med 210:1855–1869

    CAS  PubMed Central  PubMed  Google Scholar 

  • Moltedo B, Li W, Yount JS, Moran TM (2011) Unique type I interferon responses determine the functional fate of migratory lung dendritic cells during influenza virus infection. PLoS Pathog 7:e1002345

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mullbacher A, Hla RT, Museteanu C, Simon MM (1999) Perforin is essential for control of ectromelia virus but not related poxviruses in mice. J Virol 73:1665–1667

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nakano H, Lin KL, Yanagita M, Charbonneau C, Cook DN, Kakiuchi T, Gunn MD (2009) Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses. Nat Immunol 10:394–402

    CAS  PubMed Central  PubMed  Google Scholar 

  • Neyt K, Lambrecht BN (2013) The role of lung dendritic cell subsets in immunity to respiratory viruses. Immunol Rev 255:57–67

    PubMed  Google Scholar 

  • Obaru K, Fukuda M, Maeda S, Shimada K (1986) A cDNA clone used to study mRNA inducible in human tonsillar lymphocytes by a tumor promoter. J Biochem 99:885–894

    CAS  PubMed  Google Scholar 

  • O’Shea JJ, Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098–1102

    PubMed Central  PubMed  Google Scholar 

  • Ottonello L, Tortolina G, Amelotti M, Dallegri F (1999) Soluble Fas ligand is chemotactic for human neutrophilic polymorphonuclear leukocytes. J Immunol 162:3601–3606

    CAS  PubMed  Google Scholar 

  • Pang IK, Iwasaki A (2011) Inflammasomes as mediators of immunity against influenza virus. Trends Immunol 32:34–41

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pang IK, Ichinohe T, Iwasaki A (2013a) IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8(+) T cell responses to influenza A virus. Nat Immunol 14:246–253

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pang IK, Pillai PS, Iwasaki A (2013b) Efficient influenza A virus replication in the respiratory tract requires signals from TLR7 and RIG-I. Proc Natl Acad Sci USA 110:13910–13915

    CAS  PubMed Central  PubMed  Google Scholar 

  • Parameswaran N, Patial S (2010) Tumor necrosis factor-alpha signaling in macrophages. Crit Rev Eukaryot Gene Expr 20:87–103

    CAS  PubMed Central  PubMed  Google Scholar 

  • Peper RL, Van Campen H (1995) Tumor necrosis factor as a mediator of inflammation in influenza A viral pneumonia. Microb Pathog 19:175–183

    CAS  PubMed  Google Scholar 

  • Purbhoo MA, Irvine DJ, Huppa JB, Davis MM (2004) T cell killing does not require the formation of a stable mature immunological synapse. Nat Immunol 5:524–530

    CAS  PubMed  Google Scholar 

  • Roths JB, Murphy ED, Eicher EM (1984) A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice. J Exp Med 159:1–20

    CAS  PubMed  Google Scholar 

  • Rouvier E, Luciani MF, Golstein P (1993) Fas involvement in Ca(2+)-independent T cell-mediated cytotoxicity. J Exp Med 177:195–200

    CAS  PubMed  Google Scholar 

  • Russell JH, Ley TJ (2002) Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20:323–370

    CAS  PubMed  Google Scholar 

  • Said-Sadier N, Ojcius DM (2012) Alarmins, inflammasomes and immunity. Biomed J 35:437–449

    PubMed Central  PubMed  Google Scholar 

  • Schneider P, Holler N, Bodmer JL, Hahne M, Frei K, Fontana A, Tschopp J (1998) Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J Exp Med 187:1205–1213

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schreibelt G, Klinkenberg LJ, Cruz LJ, Tacken PJ, Tel J, Kreutz M, Adema GJ, Brown GD, Figdor CG, de Vries IJ (2012) The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. Blood 119:2284–2292

    CAS  PubMed  Google Scholar 

  • Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, Reiner SL, Wherry EJ (2009) A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity 31:309–320

    CAS  PubMed Central  PubMed  Google Scholar 

  • Siegel RM, Frederiksen JK, Zacharias DA, Chan FK, Johnson M, Lynch D, Tsien RY, Lenardo MJ (2000) Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288:2354–2357

    CAS  PubMed  Google Scholar 

  • Stranges PB, Watson J, Cooper CJ, Choisy-Rossi CM, Stonebraker AC, Beighton RA, Hartig H, Sundberg JP, Servick S, Kaufmann G, Fink PJ, Chervonsky AV (2007) Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26:629–641

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sun J, Braciale TJ (2013) Role of T cell immunity in recovery from influenza virus infection. Curr Opin Virol 3:425–429

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sun K, Metzger DW (2008) Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat Med 14:558–564

    CAS  PubMed  Google Scholar 

  • Sun J, Madan R, Karp CL, Braciale TJ (2009) Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 15:277–284

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sun K, Torres L, Metzger DW (2010) A detrimental effect of interleukin-10 on protective pulmonary humoral immunity during primary influenza A virus infection. J Virol 84:5007–5014

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sun J, Dodd H, Moser EK, Sharma R, Braciale TJ (2011) CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol 12:327–334

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sung SS, Fu SM, Rose CE Jr, Gaskin F, Ju ST, Beaty SR (2006) A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J Immunol 176:2161–2172

    CAS  PubMed  Google Scholar 

  • Susanto O, Trapani JA, Brasacchio D (2012) Controversies in granzyme biology. Tissue Antigens 80:477–487

    CAS  PubMed  Google Scholar 

  • Thatte J, Dabak V, Williams MB, Braciale TJ, Ley K (2003) LFA-1 is required for retention of effector CD8 T cells in mouse lungs. Blood 101:4916–4922

    CAS  PubMed  Google Scholar 

  • Thomas PG, Dash P, Aldridge JR Jr, Ellebedy AH, Reynolds C, Funk AJ, Martin WJ, Lamkanfi M, Webby RJ, Boyd KL, Doherty PC, Kanneganti TD (2009) The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30:566–575

    CAS  PubMed Central  PubMed  Google Scholar 

  • Topham DJ, Doherty PC (1998) Clearance of an influenza A virus by CD4+ T cells is inefficient in the absence of B cells. J Virol 72:882–885

    CAS  PubMed Central  PubMed  Google Scholar 

  • Topham DJ, Tripp RA, Hamilton-Easton AM, Sarawar SR, Doherty PC (1996a) Quantitative analysis of the influenza virus-specific CD4+ T cell memory in the absence of B cells and Ig. J Immunol 157:2947–2952

    CAS  PubMed  Google Scholar 

  • Topham DJ, Tripp RA, Sarawar SR, Sangster MY, Doherty PC (1996b) Immune CD4+ T cells promote the clearance of influenza virus from major histocompatibility complex class II -/- respiratory epithelium. J Virol 70:1288–1291

    CAS  PubMed Central  PubMed  Google Scholar 

  • Topham DJ, Tripp RA, Doherty PC (1997) CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. J Immunol 159:5197–5200

    CAS  PubMed  Google Scholar 

  • Tsai SY, Segovia JA, Chang TH, Morris IR, Berton MT, Tessier PA, Tardif MR, Cesaro A, Bose S (2014) DAMP molecule S100A9 acts as a molecular pattern to enhance inflammation during influenza A virus infection: role of DDX21-TRIF-TLR4-MyD88 pathway. PLoS Pathog 10:e1003848

    PubMed Central  PubMed  Google Scholar 

  • Turner SJ, Olivas E, Gutierrez A, Diaz G, Doherty PC (2007) Disregulated influenza A virus-specific CD8+ T cell homeostasis in the absence of IFN-gamma signaling. J Immunol 178:7616–7622

    CAS  PubMed  Google Scholar 

  • Valitutti S, Muller S, Dessing M, Lanzavecchia A (1996) Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J Exp Med 183:1917–1921

    CAS  PubMed  Google Scholar 

  • van Gisbergen KP, Klarenbeek PL, Kragten NA, Unger PP, Nieuwenhuis MB, Wensveen FM, ten Brinke A, Tak PP, Eldering E, Nolte MA, van Lier RA (2011) The costimulatory molecule CD27 maintains clonally diverse CD8(+) T cell responses of low antigen affinity to protect against viral variants. Immunity 35:97–108

    PubMed  Google Scholar 

  • Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF (1992) Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci USA 89:4845–4849

    PubMed Central  PubMed  Google Scholar 

  • Verbist KC, Cole CJ, Field MB, Klonowski KD (2011) A role for IL-15 in the migration of effector CD8 T cells to the lung airways following influenza infection. J Immunol 186:174–182

    CAS  PubMed Central  PubMed  Google Scholar 

  • Villadangos JA, Shortman K (2010) Found in translation: the human equivalent of mouse CD8+ dendritic cells. J Exp Med 207:1131–1134

    CAS  PubMed Central  PubMed  Google Scholar 

  • Voskoboinik I, Thia MC, Fletcher J, Ciccone A, Browne K, Smyth MJ, Trapani JA (2005) Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem 280:8426–8434

    CAS  PubMed  Google Scholar 

  • Walsh CM, Matloubian M, Liu CC, Ueda R, Kurahara CG, Christensen JL, Huang MT, Young JD, Ahmed R, Clark WR (1994) Immune function in mice lacking the perforin gene. Proc Natl Acad Sci U S A 91:10854–10858

    CAS  PubMed Central  PubMed  Google Scholar 

  • Walters RW, Grunst T, Bergelson JM, Finberg RW, Welsh MJ, Zabner J (1999) Basolateral localization of fiber receptors limits adenovirus infection from the apical surface of airway epithelia. J Biol Chem 274:10219–10226

    CAS  PubMed  Google Scholar 

  • Waterhouse NJ, Sedelies KA, Browne KA, Wowk ME, Newbold A, Sutton VR, Clarke CJ, Oliaro J, Lindemann RK, Bird PI, Johnstone RW, Trapani JA (2005) A central role for Bid in granzyme B-induced apoptosis. J Biol Chem 280:4476–4482

    CAS  PubMed  Google Scholar 

  • Wells MA, Albrecht P, Ennis FA (1981) Recovery from a viral respiratory infection. I. Influenza pneumonia in normal and T-deficient mice. J Immunol 126:1036–1041

    CAS  PubMed  Google Scholar 

  • Wiley JA, Cerwenka A, Harkema JR, Dutton RW, Harmsen AG (2001) Production of interferon-gamma by influenza hemagglutinin-specific CD8 effector T cells influences the development of pulmonary immunopathology. Am J Pathol 158:119–130

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, Liebner JC, Lambkin-Williams R, Gilbert A, Oxford J, Nicholas B, Staples KJ, Dong T, Douek DC, McMichael AJ, Xu XN (2012) Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 18:274–280

    CAS  PubMed  Google Scholar 

  • Williams MA, Bevan MJ (2007) Effector and memory CTL differentiation. Annu Rev Immunol 25:171–192

    CAS  PubMed  Google Scholar 

  • Wolf AI, Buehler D, Hensley SE, Cavanagh LL, Wherry EJ, Kastner P, Chan S, Weninger W (2009) Plasmacytoid dendritic cells are dispensable during primary influenza virus infection. J Immunol 182:871–879

    CAS  PubMed  Google Scholar 

  • Yadava K, Sichelstiel A, Luescher IF, Nicod LP, Harris NL, Marsland BJ (2013) TSLP promotes influenza-specific CD8+ T-cell responses by augmenting local inflammatory dendritic cell function. Mucosal Immunol 6:83–92

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yao S, Buzo BF, Pham D, Jiang L, Taparowsky EJ, Kaplan MH, Sun J (2013) Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation. Immunity 39:833–845

    CAS  PubMed  Google Scholar 

  • Yoo JK, Kim TS, Hufford MM, Braciale TJ (2013) Viral infection of the lung: Host response and sequelae. J Allergy Clin Immunol 132:1263–1276

    CAS  PubMed  Google Scholar 

  • Yoon H, Kim TS, Braciale TJ (2010) The cell cycle time of CD8+ T cells responding in vivo is controlled by the type of antigenic stimulus. PLoS One 5:e15423

    PubMed Central  PubMed  Google Scholar 

  • Zelenay S, Keller AM, Whitney PG, Schraml BU, Deddouche S, Rogers NC, Schulz O, Sancho D, Reis e Sousa C (2012) The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J Clin Invest 122:1615–1627

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang N, Bevan MJ (2011) CD8(+) T cells: foot soldiers of the immune system. Immunity 35:161–168

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao T, Zhang H, Guo Y, Fan Z (2007) Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death. J Biol Chem 282:12104–12111

    CAS  PubMed  Google Scholar 

  • Zhong C, Li C, Wang X, Toyoda T, Gao G, Fan Z (2012) Granzyme K inhibits replication of influenza virus through cleaving the nuclear transport complex importin alpha1/beta dimer of infected host cells. Cell Death Differ 19:882–890

    CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, USA

    Matthew M Hufford & Jie Sun

  2. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, USA

    Matthew M Hufford & Jie Sun

  3. The Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, USA

    Taeg S Kim & Thomas J Braciale

  4. The Department of Pathology and Molecular Medicine, University of Virginia, Charlottesville, USA

    Taeg S Kim & Thomas J Braciale

  5. The Department of Microbiology, Immunology and Cancer Biology University of Virginia, Charlottesville, USA

    Thomas J Braciale

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  1. Matthew M Hufford
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  2. Taeg S Kim
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  3. Jie Sun
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  4. Thomas J Braciale
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Correspondence to Thomas J Braciale .

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Editors and Affiliations

  1. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

    Michael B. A. Oldstone

  2. IDepartment of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA

    Richard W. Compans

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Hufford, M.M., Kim, T.S., Sun, J., Braciale, T.J. (2014). The Effector T Cell Response to Influenza Infection. In: Oldstone, M., Compans, R. (eds) Influenza Pathogenesis and Control - Volume II. Current Topics in Microbiology and Immunology, vol 386. Springer, Cham. https://doi.org/10.1007/82_2014_397

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