HLA-A2.1-RESTRICTED EDUCATION AND CYTOLYTIC ACTIVITY OF CD8(-LYMPHOCYTES FROM BETA-2-MICROGLOBULIN (BETA-2M) HLA-A2.1 MONOCHAIN TRANSGENIC H-2D(B) BETA-2M DOUBLE KNOCKOUT MICE() T)

Three different HLA-A2.1 monochains were engineered in which either th e human or mouse beta 2-microglobulin (beta 2m) is covalently linked t o 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, transmembra ne, and cytoplasmic domains, and MHD, homologous to HHD but linked to the mouse beta 2m(b). The cell surface expression and immunological ca pacities 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 ed ucated on the transgenic human molecule. Consequently, infected HHD, H -2D(b-/-) beta 2m(-/-) mice generate only HLA-A2.1-restricted CD8(+) C TL responses against influenza A and vaccinia viruses. Interestingly, the CTL response to influenza A virus is mostly, if not exclusively, d irected to the 58-66 matrix peptide which is the HLA-A2.1-restricted i mmunodominant epitope in humans. Such mice might constitute a versatil e animal model for the study of HLA-A2.1-restricted CTL responses of v accine interest.