PMID:21531896

Citation	James, EA, DeVoti, JA, Rosenthal, DW, Hatam, LJ, Steinberg, BM, Abramson, AL, Kwok, WW and Bonagura, VR (2011) Papillomavirus-specific CD4+ T cells exhibit reduced STAT-5 signaling and altered cytokine profiles in patients with recurrent respiratory papillomatosis. J. Immunol. 186:6633-40
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.
Links	PubMed PMC3124771 Online version:10.4049/jimmunol.1004181
Keywords	Amino Acid Sequence; CD4-Positive T-Lymphocytes/drug effects; CD4-Positive T-Lymphocytes/immunology; CD4-Positive T-Lymphocytes/metabolism; Cell Line; Cells, Cultured; Cytokines/immunology; Cytokines/metabolism; Epitopes, T-Lymphocyte/immunology; Flow Cytometry; HLA-DR Antigens/immunology; HLA-DR alpha-Chains; HLA-DRB1 Chains; Host-Pathogen Interactions/immunology; Human papillomavirus 11/immunology; Human papillomavirus 11/physiology; Interferon-gamma/immunology; Interferon-gamma/metabolism; Interleukin-13/immunology; Interleukin-13/metabolism; Interleukin-2/immunology; Interleukin-2/metabolism; Interleukin-2/pharmacology; Molecular Sequence Data; Oncogene Proteins, Viral/chemistry; Oncogene Proteins, Viral/immunology; Papillomavirus Infections/immunology; Papillomavirus Infections/metabolism; Papillomavirus Infections/virology; Peptides/immunology; Phosphorylation/immunology; Respiratory Tract Infections/immunology; Respiratory Tract Infections/metabolism; Respiratory Tract Infections/virology; STAT5 Transcription Factor/immunology; STAT5 Transcription Factor/metabolism; Signal Transduction/drug effects; Signal Transduction/immunology; Tumor Necrosis Factor-alpha/immunology; Tumor Necrosis Factor-alpha/metabolism; Viral Proteins/chemistry; Viral Proteins/immunology
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status

References

See Help:References for how to manage references in GONUTS.