Failure of gamma interferon but not interleukin-10 expression in response to human papillomavirus type 11 E6 protein in respiratory papillomatosis.
Recurrent respiratory papillomatosis (RRP) is a chronic, debilitating disease of the upper airway caused by human papillomavirus type 6 (HPV-6) or HPV-11. We describe responses of peripheral blood mononuclear cells (PBMC) and T cells from RRP patients and controls to the HPV-11 early proteins E6 and E7. PBMC were exposed in vitro to purified E6 or E7 proteins or transduced with fusion proteins containing the first 11 amino acids of the human immunodeficiency virus type 1 protein tat fused to E6 or E7 (tat-E6/tat-E7). T(H)1-like (interleukin-2 [IL-2], gamma interferon [IFN-gamma], IL-12, and IL-18), and T(H)2-like (IL-4 and IL-10) cytokine mRNAs were identified by reverse transcription-PCR, and IFN-gamma and IL-10 cytokine-producing cells were identified by enzyme-linked immunospot assay. These studies show that HPV-11 E6 skews IL-10-IFN-gamma expression by patients with RRP toward greater expression of IL-10 than of IFN-gamma. In addition, there is a general cytokine hyporesponsiveness to E6 that is more prominent for T(H)1-like cytokine expression by patients with severe disease. Patients showed persistent IL-10 cytokine expression by the nonadherent fraction of PBMC when challenged with E6 and tat-E6, and, in contrast to controls, both T cells and non-T cells from patients expressed IL-10. However, E7/tat-E7 cytokine responses in patients with RRP were similar to those of the controls. In contrast, E6 inhibited IL-2 and IL-18 mRNA expression that would further contribute to a cytokine microenvironment unfavorable to HPV-specific, T-cell responses that should control persistent HPV infection. In summary, E6 is the dominant inducer of cytokine expression in RRP, and it induces a skewed expression of IL-10 compared to the expression of IFN-gamma.
DeVoti
James A
JA
Division of Allergy and Immunology, Department of Pediatrics, Long Island Jewish Medical Center and North Shore Long-Island Jewish Research Institute, New Hyde Park, New York 11040, USA.
Steinberg
Bettie M
BM
Rosenthal
David W
DW
Hatam
Lynda
L
Vambutas
Andrea
A
Abramson
Allan L
AL
Shikowitz
Mark J
MJ
Bonagura
Vincent R
VR
D000328:Adult; D017252:CD3 Complex / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D015696:Gene Products, tat / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D018189:Immunomagnetic Separation; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007822:Laryngeal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D010212:Papilloma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D017252:CD3 Complex; C472562:CD3delta antigen; C469553:E6 protein, Human papillomavirus type 11; D015696:Gene Products, tat; D020382:Interleukin-18; D007376:Interleukin-2; D007378:Interleukins; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; D007371:Interferon-gamma