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2 Microglobulin (
2m)
HLA-A2.1 Monochain Transgenic H-2Db
2m
Double Knockout Mice
By


From the * Institut Pasteur, Département SIDA-Rétrovirus, Unité d'Immunité Cellulaire Antivirale,
75724 Paris Cedex 15, France; and Three different HLA-A2.1 monochains were engineered in which either the human or mouse
Gene Targeting Laboratory, Centre for Genome Research,
University of Edinburgh, Edinburgh EH9 3JQ, United Kingdom
2-microglobulin (
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-2Db
3, transmembrane, and cytoplasmic domains, and MHD, homologous to HHD but linked to the mouse
2mb.
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-2Db
/
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-2Db
/
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.
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