Comparison of cervical and blood T‐cell responses to human papillomavirus‐16 in women with human papillomavirus‐associated cervical intraepithelial neoplasia

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Abstract
Human papillomaviruses (HPVs) are obligate epithelial pathogens and typically cause localized mucosal infections. We therefore hypothesized that T‐cell responses to HPV antigens would be greater at sites of pathology than in the blood. Focusing on HPV‐16 because of its association with cervical cancer, the magnitude of HPV‐specific T‐cell responses at the cervix was compared with those in the peripheral blood by intracellular cytokine staining following direct ex vivo stimulation with both virus‐like particles assembled from the major capsid protein L1, and the major HPV oncoprotein, E7. We show that both CD4+ and CD8+ T cells from the cervix responded to the HPV‐16 antigens and that interferon‐γ (IFN‐γ) production was HPV type‐specific. Comparing HPV‐specific T‐cell IFN‐γ responses at the cervix with those in the blood, we found that while CD4+ and CD8+ T‐cell responses to L1 were significantly correlated between compartments (P = 0·02 and P = 0·05, respectively), IFN‐γ responses in both T‐cell subsets were significantly greater in magnitude at the cervix than in peripheral blood (P = 0·02 and P = 0·003, respectively). In contrast, both CD4+ and CD8+ T‐cell IFN‐γ responses to E7 were of similar magnitude in both compartments and CD8+ responses were significantly correlated between these distinct immunological compartments (P = 0·04). We therefore show that inflammatory T‐cell responses against L1 (but not E7) demonstrate clear compartmental bias and the magnitude of these responses do reflect local viral replication but that correlation of HPV‐specific responses between compartments indicates their linkage.

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