title: CD1d, a sentinel molecule bridging innate and adaptive immunity, is downregulated by the human papillomavirus (HPV) E5 protein: a possible mechanism for immune evasion by HPV.
abstract: CD1d and CD1d-restricted natural killer T (NKT) cells serve as a natural bridge between innate and adaptive immune responses to microbes. CD1d downregulation is utilized by a variety of microbes to evade immune detection. We demonstrate here that CD1d is downregulated in human papillomavirus (HPV)-positive cells in vivo and in vitro. CD1d immunoreactivity was strong in HPV-negative normal cervical epithelium but absent in HPV16-positive CIN1 and HPV6-positive condyloma lesions. We used two cell lines for in vitro assay; one was stably CD1d-transfected cells established from an HPV-negative cervical cancer cell line, C33A (C33A/CD1d), and the other was normal human vaginal keratinocyte bearing endogenous CD1d (Vag). Flow cytometry revealed that cell surface CD1d was downregulated in both C33A/CD1d and Vag cells stably transfected with HPV6 E5 and HPV16 E5. Although the steady-state levels of CD1d protein decreased in both E5-expressing cell lines compared to empty retrovirus-infected cells, CD1d mRNA levels were not affected. Confocal microscopy demonstrated that residual CD1d was not trafficked to the E5-expressing cell surface but colocalized with E5 near the endoplasmic reticulum (ER). In the ER, E5 interacted with calnexin, an ER chaperone known to mediate folding of CD1d. CD1d protein levels were rescued by the proteasome inhibitor, MG132, indicating a role for proteasome-mediated degradation in HPV-associated CD1d downregulation. Taken together, our data suggest that E5 targets CD1d to the cytosolic proteolytic pathway by inhibiting calnexin-related CD1d trafficking. Finally, CD1d-mediated production of interleukin-12 from the C33A/CD1d cells was abrogated in both E5-expressing cell lines. Decreased CD1d expression in the presence of HPV E5 may help HPV-infected cells evade protective immunological surveillance.
authors.affiliation: Department of Obstetrics and Gynecology, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Miura
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Schust
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.forename: Terufumi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Yuki
authors.initials: Y
authors.lastname: Iwasawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagamatsu
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Adachi
authors.forename: Ayako
authors.initials: A
authors.lastname: Tomio
authors.forename: Kensuke
authors.initials: K
authors.lastname: Tomio
authors.forename: Satoko
authors.initials: S
authors.lastname: Kojima
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yasugi
authors.forename: Shiro
authors.initials: S
authors.lastname: Kozuma
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taketani
mesh_terms: D056704:Adaptive Immunity; D052685:Alphapapillomavirus / Q000235:genetics / Q000276:immunology*; D055610:Antigens, CD1d / Q000276:immunology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D006801:Humans; D057131:Immune Evasion; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology; D000086082:Viroporin Proteins
chemical_list: D055610:Antigens, CD1d; D009856:Oncogene Proteins, Viral; C526877:CD1D protein, human; C083104:E5 protein, Human papillomavirus type 6; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins
references.citation: Immunology. 1993 Dec;80(4):561-5
references.pmid: 7508419
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13938-43
references.pmid: 10570177
references.citation: J Virol. 1993 Oct;67(10):6170-8
references.pmid: 7690419
references.citation: Nat Immunol. 2006 Aug;7(8):835-42
references.pmid: 16845396
references.citation: Curr Top Microbiol Immunol. 2007;314:215-50
references.pmid: 17593663
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11811-6
references.pmid: 16091469
references.citation: Virus Res. 2002 Sep;88(1-2):103-17
references.pmid: 12297330
references.citation: Virology. 2009 Feb 20;384(2):410-4
references.pmid: 18986661
references.citation: N Engl J Med. 1998 Feb 12;338(7):423-8
references.pmid: 9459645
references.citation: Virology. 2005 Jul 5;337(2):242-52
references.pmid: 15916790
references.citation: J Immunol. 2005 Sep 1;175(5):3197-206
references.pmid: 16116210
references.citation: Nat Immunol. 2003 Dec;4(12):1230-7
references.pmid: 14578883
references.citation: J Immunol. 2000 Oct 1;165(7):4076-85
references.pmid: 11034419
references.citation: J Virol. 1995 May;69(5):3185-92
references.pmid: 7707548
references.citation: Infect Immun. 2008 Jul;76(7):3011-8
references.pmid: 18458073
references.citation: Nat Rev Immunol. 2003 Feb;3(2):133-46
references.pmid: 12563297
references.citation: Hum Pathol. 1992 Feb;23(2):117-28
references.pmid: 1310950
references.citation: Annu Rev Immunol. 2004;22:817-90
references.pmid: 15032598
references.citation: J Cell Biol. 2000 Jan 24;148(2):305-15
references.pmid: 10648563
references.citation: J Med Microbiol. 2006 Sep;55(Pt 9):1175-1185
references.pmid: 16914646
references.citation: J Immunol. 1991 Oct 15;147(8):2518-24
references.pmid: 1717564
references.citation: Virus Res. 2006 Feb;115(2):158-68
references.pmid: 16168512
references.citation: Biol Reprod. 1999 Feb;60(2):508-14
references.pmid: 9916021
references.citation: Oncogene. 2002 Nov 7;21(51):7808-16
references.pmid: 12420217
references.citation: J Immunol. 2002 Mar 1;168(5):2424-32
references.pmid: 11859134
references.citation: J Biol Chem. 2007 Mar 9;282(10):7368-75
references.pmid: 17215251
references.citation: J Gen Virol. 2004 Oct;85(Pt 10):2809-2814
references.pmid: 15448341
references.citation: Oncogene. 2003 Aug 11;22(33):5201-7
references.pmid: 12910257
references.citation: J Biol Chem. 2002 Nov 22;277(47):44838-44
references.pmid: 12239218
references.citation: J Biol Chem. 1999 Apr 2;274(14):9289-95
references.pmid: 10092605
references.citation: Nature. 2005 Mar 24;434(7032):525-9
references.pmid: 15791258
references.citation: Semin Immunol. 2000 Dec;12(6):543-50
references.pmid: 11145860
references.citation: Virol J. 2007 Oct 30;4:116
references.pmid: 17971213
references.citation: Int J Cancer. 2005 Jan 10;113(2):276-83
references.pmid: 15386416
references.citation: Int J Cancer. 2006 Nov 1;119(9):2105-12
references.pmid: 16823848
references.citation: Infect Immun. 2003 Oct;71(10):5447-55
references.pmid: 14500461
references.citation: Immunity. 2000 Feb;12(2):211-21
references.pmid: 10714687
references.citation: J Clin Invest. 2005 May;115(5):1369-78
references.pmid: 15864354
references.citation: J Clin Microbiol. 2000 Jan;38(1):357-61
references.pmid: 10618116
references.citation: Nat Rev Cancer. 2002 May;2(5):342-50
references.pmid: 12044010
references.citation: Oncogene. 2002 Jan 10;21(2):248-59
references.pmid: 11803468
references.citation: J Immunol. 2005 Sep 15;175(6):3584-93
references.pmid: 16148102
references.citation: Science. 1994 Jul 8;265(5169):259-62
references.pmid: 7517575
references.citation: J Immunol. 2004 Apr 15;172(8):4667-71
references.pmid: 15067039