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+ Th1 cells. HLA-DR3-restricted Th1 cells respond to a subset of mycobacterial antigens, including the immunodominant hsp65, and recognize a single epitope in hsp65, notably p1-20. Altered peptide ligands (APL) of p1-20 can inhibit p1-20/hsp65-induced proliferation of DR3-restricted T cells in an allele specific manner in vitro. In order to develop a preclinical model in which p1-20 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.Ab0 mice recognized precisely the same p1-20 epitope as DR3-restricted human T cells, whereas DQ8.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, Ab0 mice provide a novel, preclinical model system to analyze APL and vaccines in the context of HLA polymorphism.
Geluk
A
A
Department of Immunohematology and Blood Bank, University Hospital Leiden, The Netherlands. Geluk@Rullf2.Medfac.Leidenuniv.nl
Taneja
V
V
van Meijgaarden
K E
KE
de Vries
R R
RR
David
C S
CS
Ottenhoff
T H
TH
D000818:Animals; D001426:Bacterial Proteins; D018834:Chaperonin 60; D018833:Chaperonins / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics*; D000949:Histocompatibility Antigens Class II; D006801:Humans; D016056:Immunodominant Epitopes; D007167:Immunotherapy; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009161:Mycobacterium / Q000276:immunology; D011110:Polymorphism, Genetic; D018417:Th1 Cells / Q000276:immunology; D014612:Vaccines
D001426:Bacterial Proteins; D018834:Chaperonin 60; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D014612:Vaccines; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins