Nonspecific down-regulation of CD8(+) T-cell responses in mice expressing human papillomavirus type 16 E7 oncoprotein from the keratin-14 promoter

The E7 oncoprotein of human papillomavirus 16 (HPV16) transforms basal and suprabasal cervical epithelial cells and is a tumor-specific antigen in cer vical carcinoma, to which immunotherapeutic strategies aimed at cytotoxic T -lymphocyte (CTL) induction are currently directed. By quantifying major hi stocompatibility complex class I tetramer-binding T cells and CTL in mice e xpressing an HPV16 E7 transgene from the keratin-l l (K14) promoter in basa l and suprabasal keratinocytes and in thymic cortical epithelium, we show t hat antigen responsiveness of both E7- and non-E7-specific CD8(+) cells is down-regulation compared to non-E7 transgenic control mice. We show that th e effect is specific for E7, and not another transgene, expressed from the K14 promoter, Down-regulation did not involve deletion of CD8(+) T cells of high affinity or high avidity, and T-cell receptor (TCR) VP-chain usage an d TCR receptor density were similar in antigen-responsive cells from E7 tra nsgenic and non-E7 transgenic mice. These data indicate that E7 expressed c hronically from the K14 promoter nonspecifically down-regulates CD8+ T-cell responses. The in vitro data correlated with the failure of immunized E7 t ransgenic mice to control the growth of an E7-expressing tumor challenge, W e have previously shown that E7-directed CTL down-regulation correlates wit h E7 expression in peripheral but not thymic epithelium (T, Dean et al., J, Virol. 73:6166-6170, 1999), The findings have implications for the immunol ogical consequences of E7-expressing tumor development and E7-directed immu nization strategies. Generically, the findings illustrate a T-cell immunomo dulatory function for a virally encoded human oncoprotein.