Induction of CTL response by a minimal epitope vaccine in HLA A∗0201/DR1 transgenic mice: dependence on HLA class II restricted T H response

Abstract

CTL play a pivotal role in the immune response during viral infections. In this study, the HLA class II restricted T H requirement for optimal in vivo induction of HLA class I restricted CTL responses has been investigated. Towards this goal, transgenic mice expressing both HLA class I (A∗0201 or A2.1) and class II (DRB1∗0101 or DR1) molecules have been derived. Immunization of these mice with an HLA A∗0201-restricted and CMV-specific CTL epitope (pp65 495–503), and either of three different tetanus toxin-derived MHC class II-binding T H epitopes, resulted in a vigorous CTL response. CTL specific for the pp65 495–503 epitope were dramatically enhanced in mice expressing both the HLA-DR1 and HLA-A∗0201 transgenes. Notably, preinjection of three TT peptides (TT 639–652, TT 830–843, and TT 947–967) increased the capability of HLA A∗0201/DR1 Tg mice to respond to subsequent immunization with the T H + CTL peptide mixture. These results indicate that the use of HLA A∗0201/DR1 Tg mice constitute a versatile model system (in lieu of immunizing humans) for the study of both HLA class I and class II restricted T-cell responses. These studies provide a rational model for the design and assessment of new minimal-epitope vaccines based on their in vivo induction of a pathogen-specific CTL response.