Interferon‐γ and IL‐5 associated cell‐mediated immune responses to HPV16 E2 and E6 distinguish between persistent oral HPV16 infections and noninfected mucosa

OBJECTIVES: Natural history of human papillomavirus (HPV) infection in the head and neck region is poorly understood, and their impact on collective HPV‐specific immunity is not known. MATERIALS AND METHODS: In this study, we have performed a systematic analysis of HPV16‐specific cell‐mediated immunity (CMI) in 21 women with known oral and genital HPV DNA status and HPV serology (Ab) based on 6‐year follow‐up data. These women being a subgroup from the Finnish Family HPV Study were recalled for blood sampling to be tested for their CMI‐responses to HPV16 E2, E6, and E7 peptides. RESULTS: The results showed that HPV16 E2‐specific lymphocyte proliferation was more prevalent in women who tested HPV16 DNA negative in oral mucosa and were either HPV16 seropositive or negative than in HPV16 DNA+/Ab+ women (p = 0.046 and p = 0.035). In addition, the HPV16 DNA−/Ab− women most often displayed E6‐specific proliferation (p = 0.020). Proportional cytokine profiles indicated that oral HPV16‐negative women were characterized by prominent IFN‐γ and IL‐5 secretion not found in women with persisting oral HPV16 (p = 0.014 and p = 0.040, respectively). CONCLUSIONS: Our results indicate that the naturally arising immune response induced by oral HPV infections displays a mixed Th1/Th2/Th17 cytokine profile while women with persisting oral HPV16 might have an impaired HPV16‐specific CMI, shifted partly toward a Th2 profile, similarly as seen earlier among patients with high‐grade genital HPV lesions. Thus, the lack of HPV 16 E2 and E6 specific T memory cells and Th2 cytokines might also predispose women for persistent oral HPV16 infection which might be related to the risk of cancer.