HLA-DR/DQ Transgenic, class II deficient mice as a novel model to select for HSP T cell epitopes with immunotherapeutic or preventative vaccine potential

Protective immunity against mycobacteria is dependent on antigen/MHC class II specific, CD4⁺ Thl cells. HLA-DR3-restricted Thl cells respond to a subset of mycobacterial antigens, including the immunodominanthsp65, and recognize a single epitope in hsp65, notably p 1 -20. Altered peptide ligands (APL) of p 1 -20 can inhibit p l -20/hsp65-induced proliferation of DR3-restricted T cells in an allele specific manner in vitro. In order to develop a preclinical model in which p 1-20 APL can be tested in vivo in the context of HLA, we have used murine class II deficient, HLA transgenic (Ab⁰) mice, in which all CD4⁺ T cells are restricted by the tg HLA molecule. BCG-immunized DR3.Ab⁰ and DQ8.Ab⁰ mice both responded well to hsp65. Furthermore, DR3.Ab° mice recognized precisely the same pl-20 epitope as DR3-restricted human T cells, whereas DR3.Ab⁰ mice responded to a different set of hsp65 peptides. This shows that (i) the same immunodominant protein and peptide epitope are recognized by T cells from DR3.Ab⁰ mice and DR3⁺ humans and (ii) indicates the major role of HLA-polymorphism in controlling the human T cell response to mycobacterial antigens. Thus, HLA-transgenic, Ab⁰mice provide a novel, preclinical model system to analyze APL and vaccines in the context of HLA polymorphism.