Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 10, Pages 4748-4757Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1303190
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Funding
- National Institutes of Health [R01 CA74397, RC2 CA148298]
- Southern California Clinical and Translational Science Institute (National Institutes of Health/National Center for Research Resources/National Center for Advancing Translational Sciences) [TL1TR000132]
- National Institutes of Health from the National Cancer Institute through the Norris Comprehensive Cancer Center Heidelberger Award [5P30CA014089-37]
- Karl H. and Ruth M. Balz Trust
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High-risk human papillomaviruses (HPVs) are sexually transmitted viruses causally associated with several cancers. During its natural life cycle, HPV16, the most common high-risk genotype, infects the epithelial basal cells in a process facilitated through a recently identified receptor, the annexin A2 heterotetramer (A2t). During infection, HPV16 also interacts with Langerhans cells (LC), the APC of the epithelium, inducing immune suppression, which is mediated by the HPV16 L2 minor capsid protein. Despite the importance of these virus-immune cell interactions, the specific mechanisms of HPV16 entry into LC and HPV16-induced immune suppression remain undefined. An N-terminal peptide of HPV16 L2 (aa 108-126) has been shown to specifically interact with A2t. In this study, we show that incubation of human LC with this peptide blocks binding of HPV16. Inhibiting this interaction with an A2t ligand or by small interfering RNA downregulation of A2t significantly decreases HPV16 internalization into LC in an L2-dependent manner. A2t is associated with suppression of LC maturation as demonstrated through attenuated secretion of Th1-associated cytokines and decreased surface expression of MHC class II on LC exposed to A2t. Conversely, small molecule inhibition of A2t prevents HPV16-induced suppression of LC immune function as indicated by significantly increased secretion of inflammatory cytokines and surface expression of CD86 in HPV16 treated LC pre-exposed to A2t inhibitors. These results demonstrate that HPV16 suppresses LC maturation through an interaction with A2t, revealing a novel role for this protein.
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