HLA-A2.1-restricted education and cytolytic activity of CD8(+) T lymphocytes from beta 2 microglobulin (beta 2m) HLA-A2.1 monochain transgenic H-2D(b) beta 2m double knockout mice

Three different HLA-A2.1 monochains were engineered in which either the human or mouse beta 2-microglobulin (beta 2m) is covalently linked to the NH2 terminus of the heavy chain by a 15-amino acid long peptide: HHH, entirely human, HHD, with the mouse H-2D(b) alpha 3, transmembrane, and cytoplasmic domains, and MHD, homologous to HHD but linked to the mouse beta 2m(b). The cell surface expression and immunological capacities of the three monochains were compared with transfected cells, and the selected HHD construct was introduced by transgenesis in H-2D(b-/-) beta 2m(-/-) double knockout mice. Expression of this monochain restores a sizable peripheral CD8(+) T cell repertoire essentially educated on the transgenic human molecule. Consequently, infected HHD, H-2D(b-/-) beta 2m(-/-) mice generate only HLA-A2.1-restricted CD8(+) CTL responses against influenza A and vaccinia viruses. Interestingly, the CTL response to influenza A virus is mostly, if not exclusively, directed to the 58-66 matrix peptide which is the HLA-A2.1-restricted immunodominant epitope in humans. Such mice might constitute a versatile animal model for the study of HLA-A2.1-restricted CTL responses of vaccine interest.