Altered major histocompatibility complex class II peptide loading in H2-O-deficient mice.
The biosynthesis of MHC class II/peptide complexes involves classical, cell surface MHC products as well as the intracellular component H2-M, required for the removal of invariant chain-derived CLIP and for peptide loading. The function of another intracellular class II heterodimer, H2-O, is the matter of some controversy. The physical association of H2-O with H2-M and co-localization in class II+ vesicles suggest a related function in peptide exchange. Furthermore, the distinctive thymic distribution of H2-O raises the possibility of a specialized role in T cell thymic selection. To investigate the role of H2-O in vivo we generated mice carrying a targeted disruption in the H2-Oa gene. No evidence was obtained for a defect in removal of CLIP. However, the array of endogenous peptides bound by class II was altered and a defect in antigen presentation through H2-A to T cells was seen on the 129/Sv/ C57BL/6 mixed strain background but not in 129/Sv pure strain mice. Furthermore, H2-O-null mice showed enhanced selection of CD4+ single positive thymocytes. The findings indicate that H2-O interacts with H2-M in peptide editing but that the genetic background in which H2-O deficiency is manifest is also important. Overall, the experiments indicate that H2-O/HLA-DO should be regarded as neither up-regulating nor down-regulating the DM-dependent release of CLIP, but as a modulator of peptide editing, determining the presenting cell type specific peptide profile able to retain stability in the class II groove.
Perraudeau
M
M
Transplantation Biology Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, GB.
Taylor
P R
PR
Stauss
H J
HJ
Lindstedt
R
R
Bygrave
A E
AE
Pappin
D J
DJ
Ellmerich
S
S
Whitten
A
A
Rahman
D
D
Canas
B
B
Walport
M J
MJ
Botto
M
M
Altmann
D M
DM
D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D019281:Dimerization; D005260:Female; D005802:Genes, MHC Class II; D005838:Genotype; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000941:Antigens; D000944:Antigens, Differentiation, B-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; C416186:H-2O antigen; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C045084:invariant chain