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Department of Immunology, Mayo Clinic and Medical School, Rochester, MN 55905
Optimum function of HLA-DR molecules in transgenic mice requires
efficient interaction between the class II molecules on APCs and CD4 on
T cells. Residues 110 and 139 of the second domain of class II
molecules are considered to be critical for recognition of CD4. We
generated an HLA-DR4ß(NT) transgene construct in which positions 110
and 139 were altered to resemble endogenous mouse H2 Aß molecules.
This construct was introduced into (B10 x SWR) embryos, and
DR4ß(NT) transgenic mice were produced. The transgene was transferred
into B10.RFB3 (Eß0 E
p) mice. The
transgene-encoded DR4ß molecules paired with endogenous E chains
to form stable DR4ß/E dimers expressed on the cell surface. The
hybrid dimers showed similar Ag-binding specificity to HLA-DR4
molecules and positively selected CD4+ T cells in vivo.
Immunization of HLA-DR4ß(NT) transgenic mice with DR4-restricted
peptides induced T cell proliferation in vitro. While the purified T
cells from DR4ß(NT) transgenic mice responded strongly to the
HA(307–319) presented by M12C3 transfectants expressing altered
DR4ß/E heterodimers, the response to the same peptides presented
by transfectants expressing wild-type DR4ß/E molecules was
substantially reduced. Taken together, these data confirmed in vitro
studies on the importance of these residues in CD4-MHC class II
interaction. The altered HLA-DR4ß transgenic mice were able to
overcome the species barrier and generate efficient HLA-DR4-restricted
CD4-specific immune responses. Thus, residues 110 and 139 were critical
for the interaction of class II with CD4 T cells during thymic
selection as well as peripheral immune
responses.
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