Major histocompatibility complex (MHC) class I is a major host defense mechanism against viral infections such as type 16 and type 18 of the human papillomavirus (HPV). Here, we found that the E6 oncogene from HPV16, but not HPV18, suppressed MHC I expression. Ectopic expression of HPV16E6 in HeLa cells, which are infected with HPV18, suppressed MHC I expression, and that knockdown by antisense or siRNA of the HPV16E6 strongly enhanced MHC I expression in Caski cells, which are infected with HPV18, but not HPV16. The expression of HPV16E6 strongly enhanced cellular resistance to cytotoxic T lymphocytes (CTLs)-mediated lytic activity, and knockdown of HPV16E6 by antisense had the opposite effect. The regulation of HPV16E6-mediated MHC I suppression might be through the regulation of lymphotoxin (LT) and its receptor, LT beta R. In addition, cells from the spleen and liver of LT alpha- or LT beta R-deficient mice showed increased MHC I expression. Overall, these results demonstrated that the E6 oncogene of HPV16 might play an important role in cell transformation and cancer development through LT-mediated MHC I downregulation in humans. (C) 2011 Elsevier Inc. All rights reserved.