title: Beyond the classical: influenza virus and the elucidation of alternative MHC class II-restricted antigen processing pathways.
abstract: CD4+ T cells (T(CD4+)) are activated by peptides, generally 13-17 amino acids in length, presented at the cell surface in combination with highly polymorphic MHC class II molecules. According to the classical model, these peptides are generated by endosomal digestion of internalized antigen and loaded onto MHC class II molecules in the late endosome. Historically, this "exogenous" pathway has been defined through the extensive use of purified proteins. However, the relatively recent use of clinically relevant antigens, those of influenza virus in our case, has revealed several additional pathways of peptide production, including some that are truly "endogenous", entailing synthesis of the protein within the infected cell. Indeed, some peptides appear to be created only via endogenous processing. The cell biology that underlies these alternative pathways remains poorly understood as do their relative contributions to defence against infectious agents and cancer, and the triggering of autoimmune diseases.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. Laurence.Eisenlohr@jefferson.edu
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Eisenlohr
authors.forename: Nancy
authors.initials: N
authors.lastname: Luckashenak
authors.forename: Sebastien
authors.initials: S
authors.lastname: Apcher
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miller
authors.forename: Gomathinayagam
authors.initials: G
authors.lastname: Sinnathamby
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D011992:Endosomes / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007251:Influenza, Human / Q000276:immunology*; D042541:Intracellular Space; D051379:Mice; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D000949:Histocompatibility Antigens Class II
references.citation: Curr Opin Immunol. 2010 Feb;22(1):89-93
references.pmid: 20149615
references.citation: Cell Immunol. 1993 Apr 15;148(1):60-70
references.pmid: 8495491
references.citation: Mol Immunol. 1997 Apr;34(6):471-80
references.pmid: 9307063
references.citation: Immunology. 2007 Feb;120(2):207-16
references.pmid: 17116173
references.citation: J Exp Med. 2000 May 1;191(9):1513-24
references.pmid: 10790426
references.citation: J Biol Chem. 1999 Feb 5;274(6):3363-71
references.pmid: 9920878
references.citation: Annu Rev Genet. 2009;43:67-93
references.pmid: 19653858
references.citation: Int Immunol. 1992 Oct;4(10):1113-21
references.pmid: 1336977
references.citation: Immunol Res. 2001;23(2-3):205-14
references.pmid: 11444385
references.citation: Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3290-4
references.pmid: 1707537
references.citation: Traffic. 2000 Feb;1(2):152-60
references.pmid: 11208095
references.citation: J Exp Med. 1984 Nov 1;160(5):1316-37
references.pmid: 6436430
references.citation: J Virol. 2007 Aug;81(15):8225-35
references.pmid: 17522213
references.citation: Immunol Rev. 2005 Oct;207:218-28
references.pmid: 16181339
references.citation: Immunol Rev. 1978;40:227-55
references.pmid: 313896
references.citation: Immunol Rev. 1990 Dec;118:21-35
references.pmid: 2079327
references.citation: Eur J Immunol. 1994 Jul;24(7):1632-9
references.pmid: 8026524
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20465-70
references.pmid: 21059907
references.citation: Cell Immunol. 1970 Jul;1(2):207-18
references.pmid: 5523578
references.citation: Nature. 1998 Mar 19;392(6673):245-52
references.pmid: 9521319
references.citation: Adv Immunol. 2005;86:241-305
references.pmid: 15705424
references.citation: Cell Immunol. 1987 Dec;110(2):431-5
references.pmid: 2961464
references.citation: Biochemistry. 1963 Sep-Oct;2:971-9
references.pmid: 14087390
references.citation: Immunol Cell Biol. 2008 May-Jun;86(4):353-62
references.pmid: 18268517
references.citation: Biochim Biophys Acta. 2009 Jan;1792(1):3-13
references.pmid: 19022377
references.citation: Adv Immunol. 2005;88:193-233
references.pmid: 16227091
references.citation: J Exp Med. 1989 Mar 1;169(3):921-31
references.pmid: 2784481
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13856-61
references.pmid: 9391117
references.citation: Nat Rev Immunol. 2003 Aug;3(8):621-9
references.pmid: 12974477
references.citation: Nature. 1990 Aug 9;346(6284):574-6
references.pmid: 2115981
references.citation: J Immunol. 1998 Aug 15;161(4):1599-607
references.pmid: 9712021
references.citation: Curr Opin Immunol. 2006 Feb;18(1):64-9
references.pmid: 16337363
references.citation: Eur J Immunol. 1995 Jan;25(1):48-53
references.pmid: 7843252
references.citation: J Immunol. 1988 Oct 15;141(8):2581-4
references.pmid: 2459219
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3491-6
references.pmid: 18305173
references.citation: J Immunol. 1984 Dec;133(6):3371-7
references.pmid: 6208279
references.citation: J Neuroimmunol. 1993 Jul;46(1-2):57-65
references.pmid: 7689595
references.citation: J Biol Chem. 1998 Jul 24;273(30):18734-42
references.pmid: 9668046
references.citation: Curr Top Microbiol Immunol. 2009;335:123-40
references.pmid: 19802563
references.citation: Virology. 1994 May 15;201(1):86-94
references.pmid: 7513927
references.citation: Immunol Rev. 1999 Dec;172:49-66
references.pmid: 10631936
references.citation: J Immunol. 1949 Oct;63(2):173-81
references.pmid: 15390506
references.citation: Annu Rev Microbiol. 2004;58:391-424
references.pmid: 15487943
references.citation: J Immunol. 1997 Mar 15;158(6):2670-9
references.pmid: 9058800
references.citation: J Immunol. 1981 Mar;126(3):1075-9
references.pmid: 6970212
references.citation: J Exp Med. 1978 Apr 1;147(4):1236-52
references.pmid: 306410
references.citation: Curr Top Microbiol Immunol. 2005;300:127-48
references.pmid: 16573239
references.citation: Nature. 2002 Oct 24;419(6909):845-9
references.pmid: 12397360
references.citation: Immunology. 2010 Sep;131(1):9-17
references.pmid: 20586810
references.citation: Curr Opin Immunol. 2011 Feb;23(1):88-95
references.pmid: 21112200
references.citation: Immunity. 2010 Feb 26;32(2):227-39
references.pmid: 20171125
references.citation: Transfus Med Rev. 2008 Jul;22(3):188-201
references.pmid: 18572095
references.citation: Immunol Today. 1985 Mar;6(3):101-6
references.pmid: 25291539
references.citation: Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1:1-13
references.pmid: 2700931
references.citation: Nature. 1990 Jan 4;343(6253):74-6
references.pmid: 1967486
references.citation: Eur J Immunol. 1994 Jan;24(1):247-56
references.pmid: 8020564
references.citation: Curr Opin Immunol. 2004 Feb;16(1):82-9
references.pmid: 14734114
references.citation: Cancer Res. 2002 Oct 1;62(19):5505-9
references.pmid: 12359760
references.citation: Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6886-91
references.pmid: 9192661
references.citation: Cancer Invest. 2005;23(5):413-9
references.pmid: 16193641
references.citation: J Immunol. 1991 Nov 15;147(10):3306-13
references.pmid: 1658143
references.citation: Annu Rev Immunol. 1997;15:821-50
references.pmid: 9143708
references.citation: Microb Pathog. 1992 Jan;12(1):27-38
references.pmid: 1560752
references.citation: Cell. 1991 Feb 22;64(4):767-76
references.pmid: 1847667
references.citation: Mol Immunol. 2007 Feb;44(6):1352-60
references.pmid: 16828498
references.citation: Cell Immunol. 1979 Jan;42(1):155-69
references.pmid: 312141
references.citation: Immunology. 1993 Dec;80(4):566-73
references.pmid: 7508420
references.citation: J Immunol. 1993 Dec 15;151(12):6751-6
references.pmid: 8258689
references.citation: Curr Opin Immunol. 2001 Feb;13(1):26-31
references.pmid: 11154913
references.citation: J Exp Med. 1992 Sep 1;176(3):793-8
references.pmid: 1512543
references.citation: Trends Endocrinol Metab. 2010 Mar;21(3):142-50
references.pmid: 19857975
references.citation: PLoS One. 2011 Apr 20;6(4):e18817
references.pmid: 21533087
references.citation: EMBO J. 1992 Aug;11(8):2829-39
references.pmid: 1379172
references.citation: J Immunol. 2004 Jun 1;172(11):6607-14
references.pmid: 15153475
references.citation: Eur J Immunol. 1998 Sep;28(9):2605-18
references.pmid: 9754549
references.citation: Proc Natl Acad Sci U S A. 2005 May 31;102(22):7779-80
references.pmid: 15911750
references.citation: Nature. 1983 May 5-11;303(5912):35-40
references.pmid: 6843658
references.citation: EMBO J. 1994 Jun 1;13(11):2699-707
references.pmid: 8013468
references.citation: J Immunol. 2010 Dec 1;185(11):6608-16
references.pmid: 21048109
references.citation: Nature. 1986 Aug 21-27;322(6081):687-9
references.pmid: 3489186
references.citation: Eur J Immunol. 1995 Dec;25(12):3402-11
references.pmid: 8566030
references.citation: Biochem J. 1991 Apr 1;275 ( Pt 1):165-9
references.pmid: 2018472
references.citation: J Immunol. 1985 Aug;135(2):1391-4
references.pmid: 2409149
references.citation: Nat Struct Mol Biol. 2008 Jul;15(7):690-8
references.pmid: 18596815
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12616-21
references.pmid: 9356498
references.citation: Eur J Immunol. 1999 Dec;29(12):4043-52
references.pmid: 10602015
references.citation: J Immunol. 1993 May 1;150(9):3690-7
references.pmid: 8473726
references.citation: Nature. 1992 Jun 25;357(6380):702-4
references.pmid: 1614517
references.citation: Hum Mol Genet. 2002 May 1;11(9):1107-17
references.pmid: 11978769
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14692-7
references.pmid: 8962116
references.citation: J Immunol. 1988 Feb 15;140(4):1063-8
references.pmid: 2449493
references.citation: Cell Immunol. 1992 Jan;139(1):268-73
references.pmid: 1728968
references.citation: Curr Opin Immunol. 1999 Feb;11(1):76-81
references.pmid: 10047537
references.citation: Immunol Rev. 1980;53:127-47
references.pmid: 6162776
references.citation: EMBO J. 1992 Feb;11(2):411-6
references.pmid: 1311249
references.citation: Cell. 1984 Feb;36(2):319-27
references.pmid: 6607120
references.citation: J Exp Med. 1993 Jul 1;178(1):73-85
references.pmid: 8315396
references.citation: Immunology. 2001 Apr;102(4):405-15
references.pmid: 11328374
references.citation: Nat Immunol. 2007 Jan;8(1):101-8
references.pmid: 17128277
references.citation: Science. 1990 Aug 31;249(4972):1028-30
references.pmid: 2118680
references.citation: Nat Rev Mol Cell Biol. 2008 Jul;9(7):543-56
references.pmid: 18496517
references.citation: Cell Immunol. 2000 Aug 1;203(2):75-83
references.pmid: 11006005
references.citation: J Virol. 1991 Feb;65(2):672-6
references.pmid: 1898970
references.citation: Annu Rev Immunol. 1984;2:395-428
references.pmid: 6242349
references.citation: J Immunol. 1985 Mar;134(3):1994-8
references.pmid: 3155776
references.citation: Dermatol Online J. 1999 May;5(1):7
references.pmid: 10673450
references.citation: J Immunol. 1994 May 15;152(10):4852-60
references.pmid: 8176208
references.citation: Nature. 2006 Nov 2;444(7115):115-8
references.pmid: 17051151
references.citation: Nature. 1995 Jun 22;375(6533):685-8
references.pmid: 7540727
references.citation: Nat Immunol. 2006 Jan;7(1):103-12
references.pmid: 16299505
references.citation: J Virol. 1991 Jan;65(1):364-72
references.pmid: 1702160
references.citation: Arch Biochem Biophys. 1956 Jan;60(1):171-9
references.pmid: 13283601
references.citation: J Exp Med. 2000 May 1;191(9):1499-512
references.pmid: 10790425
references.citation: Immunology. 1989 Dec;68(4):497-502
references.pmid: 2606508
references.citation: Curr Opin Cell Biol. 2008 Aug;20(4):437-44
references.pmid: 18582577
references.citation: Nat Immunol. 2008 May;9(5):558-66
references.pmid: 18376402
references.citation: Proc Natl Acad Sci U S A. 1989 Jan;86(1):282-6
references.pmid: 2492101
references.citation: Eur J Immunol. 1996 Dec;26(12):3163-9
references.pmid: 8977318
references.citation: Vaccine. 1993;11(8):795-804
references.pmid: 8356842
references.citation: Eur J Immunol. 2008 May;38(5):1225-30
references.pmid: 18389477
references.citation: Nat Immunol. 2008 Sep;9(9):981-7
references.pmid: 18711435
references.citation: Immunity. 2005 May;22(5):571-81
references.pmid: 15894275
references.citation: Annu Rev Biochem. 2001;70:777-810
references.pmid: 11395423
references.citation: J Biol Chem. 2003 Jul 4;278(27):25009-13
references.pmid: 12719433
references.citation: J Leukoc Biol. 1994 Oct;56(4):469-74
references.pmid: 7930943
references.citation: J Virol. 1989 Apr;63(4):1756-62
references.pmid: 2784508
references.citation: Nature. 1985 Apr 11-17;314(6011):537-9
references.pmid: 3157869
references.citation: Nat Immunol. 2005 Mar;6(3):287-94
references.pmid: 15711549
references.citation: Immunol Rev. 2005 Oct;207:145-57
references.pmid: 16181333
references.citation: J Immunol. 1985 Nov;135(5):2914-22
references.pmid: 3900200
references.citation: J Immunol. 1993 Sep 15;151(6):2928-42
references.pmid: 8376762
references.citation: Curr Opin Cell Biol. 2000 Aug;12(4):407-13
references.pmid: 10873820
references.citation: Curr Opin Immunol. 1997 Dec;9(6):872-83
references.pmid: 9492992
references.citation: EMBO J. 2007 Feb 7;26(3):846-54
references.pmid: 17255932
references.citation: J Immunol. 2009 Dec 1;183(11):6893-7
references.pmid: 19917682
references.citation: J Virol. 2011 Jul;85(13):6453-63
references.pmid: 21525345
references.citation: J Biol Chem. 1997 Nov 14;272(46):29127-36
references.pmid: 9360989
references.citation: Proc Natl Acad Sci U S A. 1997 May 27;94(11):5772-7
references.pmid: 9159149