SPLIT TOLERANCE TO A VIRAL-ANTIGEN EXPRESSED IN THYMIC EPITHELIUM ANDKERATINOCYTES

When expressed as a transgene from the keratin 14 (K14) promoter in an MHC class II-deficient mouse, I-Ab expressed in thymic cortical epith elium promotes positive but not negative selection of I-Ab-restricted CD4(+) T cells (Laufer, T. M. et al., Nature 1996. 383:81-85). Transge nic mice expressing the E7 protein of human papilloma virus 16 from th e K14 promoter were studied to determine the consequence of expression of a cytoplasmic/nuclear protein from the K14 promoter. K14E7-transge nic mice express E7 in the thymus and skin without evidence for autoim munity to E7. Repeated immunization of FVB(H-2(q)) or F1(C57BV6JxFVB) mice with E7 elicited similar antibody responses to the defined B cell epitopes of E7 in K14E7-transgenic and non-transgenic animals. In con trast, for each genetic background, a single immunization with E7 elic ited demonstrable T cell proliferative responses to the major promiscu ous T helper epitope of E7 in the transgenic but not the non-transgeni c animals. Further,E7-immunized non-transgenic F1 (FVBxC57BL/6J) anima ls developed strong E7-specific cytotoxic T lymphocyte (CTL) responses and were protected against challenge with E7(+) tumors, whereas simil arly immunized K14E7-transgenic animals had a markedly reduced CTL res ponse to E7 and no E7-specific tumor protection was observed, although the antibody and CTL response to ovalbumin was normal. Expression of E7 protein as a transgene from the K14 promoter in the skin and thymus thus induces E7-specific tolerance in the cytotoxic T effector repert oire, together with expansion of the E7-specific T helper repertoire. These findings demonstrate that limited tissue distribution of an auto antigen may result in ''split'' tolerance to that autoantigen.