title: Papillomavirus-specific CD4+ T cells exhibit reduced STAT-5 signaling and altered cytokine profiles in patients with recurrent respiratory papillomatosis.
abstract: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus type 6 (HPV-6) or HPV-11. Specific HLA-DR haplotypes DRB1*01:02 and DRB1*03:01 are associated with the development of RRP, disease severity, and Th2-like responses to HPV early proteins. Th1-like responses to HPV proteins have been shown to be protective in animal models. Therefore, we investigated the hypothesis that RRP patients have dysfunctional Th1-like, HPV-specific T cell responses. Using MHC class II tetramers, we identified immunogenic peptides within HPV-11 early proteins. Two distinct peptides (E6(113-132) and E2(1-20)) contained DRB1*01:02- or DRB1*03:01-restricted epitopes, respectively. An additional peptide (E2(281-300)) contained an epitope presented by both alleles. Peptide binding, tetramer, and proliferation assays identified minimal epitopes within these peptides. These epitopes elicited E2/E6-specific CD4(+) T cell responses in RRP patients and healthy control subjects, allowing the isolation of HPV-specific T cell lines using tetramers. The cytokine profiles and STAT signaling of these tetramer-positive T cells were measured to compare the polarization and responsiveness of HPV-specific T cells from patients with RRP and healthy subjects. HPV-specific IFN-γ secretion was substantially lower in T cells from RRP patients. HPV-specific IL-13 secretion was seen at modest levels in T cells from RRP patients and was absent in T cells from healthy control subjects. HPV-specific T cells from RRP patients exhibited reduced STAT-5 phosphorylation and reduced IL-2 secretion, suggesting anergy. Levels of STAT-5 phosphorylation and IFN-γ secretion could be improved through addition of IL-2 to HPV-specific T cell lines from RRP patients. Therapeutic vaccination or interventions aimed at restoring Th1-like cytokine responses to HPV proteins and reversing anergy could improve clinical outcomes for RRP patients.
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA. ejames@benaroyaresearch.org
authors.forename: Eddie A
authors.initials: EA
authors.lastname: James
authors.forename: James A
authors.initials: JA
authors.lastname: DeVoti
authors.forename: David W
authors.initials: DW
authors.lastname: Rosenthal
authors.forename: Lynda J
authors.initials: LJ
authors.lastname: Hatam
authors.forename: Bettie M
authors.initials: BM
authors.lastname: Steinberg
authors.forename: Allan L
authors.initials: AL
authors.lastname: Abramson
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Bonagura
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000276:immunology; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D054884:Host-Pathogen Interactions / Q000276:immunology; D052140:Human papillomavirus 11 / Q000276:immunology* / Q000502:physiology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000276:immunology; D030361:Papillomavirus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D010455:Peptides / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D012141:Respiratory Tract Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D050799:STAT5 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D016207:Cytokines; C117355:E2 protein, Human papillomavirus type 11; C469553:E6 protein, Human papillomavirus type 11; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D018793:Interleukin-13; D007376:Interleukin-2; D009856:Oncogene Proteins, Viral; D010455:Peptides; D050799:STAT5 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D007371:Interferon-gamma