Phenotypical and Functional Characterization of the CD8+ T Cell Repertoire of HLA-A2.1 Transgenic, H-2KbnullDbnull Double Knockout Mice

Homozygous HLA-A2.1 transgenic H-2KbnullDbnull double knockout (KO) mice were created. Their potential to develop HLA-A2. 1-restricted cytolytic responses was compared with that of their classical transgenic counterparts, which still express H-2Kb, Db molecules. On cell surfaces, both strains express similar amounts of chimeric (alpha 1 alpha 2 domains of human, alpha 3 cytoplasmic domains of mouse) HLA-A2.1 molecules in noncovalent association with mouse beta 2-microglobulin. Compared with mice that are totally deprived of histocompatibility class Ia molecules (H-2KbnullDbnull double KO), the expression of HLA-A2.1 in transgenic/double KO mice resulted in sizeable increase in the periphery of CD8+ T cells with a normally diversified TCR repertoire. A biased education in favor of HLA-A2.1, ascribable to the absence of H-2 class Ia molecules, was evidenced in these transgenic/double KO mice by their improved capacity to mount HLA-restricted cytolytic responses, regardless of whether they were virally infected or injected with synthetic epitopic peptide. HLA class I transgenic, H-2 class Ia KO mice should represent useful animal models for the preclinical evaluation of vaccine formulations aiming at the induction of HLA class I-restricted CTL responses.