HLA-DR4 (DRB1*0401) transgenic mice expressing an altered CD4-binding site: Specificity and magnitude of DR4-restricted T cell response

Shuchong Pan, Theodore Trejo, Julie Hansen, Michele Smart, Chella S. David

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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- DR4β(NT) transgene construct in which positions 110 and 139 were altered to resemble endogenous mouse H2 Aβ molecules. This construct was introduced into (B10 x SWR) embryos, and DR4β(NT) transgenic mice were produced. The transgene was transferred into B10.RFB3 (Eβ0 Eα(p)) mice. The transgene- encoded DR4β molecules paired with endogenous Eα chains to form stable DR4β/Eα 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-DR4β(NT) transgenic mice with DR4-restricted peptides induced T cell proliferation in vitro. While the purified T cells from DR4β(NT) transgenic mice responded strongly to the HA(307-319) presented by M12C3 transfectants expressing altered DR4β/Eα heterodimers, the response to the same peptides presented by transfectants expressing wild-type DR4β/Eα 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-DR4β 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.

Original languageEnglish (US)
Pages (from-to)2925-2929
Number of pages5
JournalJournal of Immunology
Volume161
Issue number6
StatePublished - Sep 15 1998

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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