Opportunities and limitations of mouse models humanized for HLA class II antigens.

Summary MHCclassIImoleculesareessentialforshapingtheCD4+ T-cell repertoire in the thymus and for selectingantigenic peptides that are presented to CD4+ T cells in theperiphery. A range of different mouse models humanized forHLA class II antigens have been developed to study theregulationofMHC-classIIrestrictedimmuneresponses.Thesemouse models have been used to identify immunodominantpeptidesthattriggerdiseasesandtocharacterizetheinteractionsof T-cell receptors with disease-associated peptides and MHCclass II molecules. Peptides presented to CD4+ T cells in thesemousemodelswereshowntobesimilartopeptidespresentedtoCD4+ T cells in patients who carry the same MHC class IIhaplotype. Opportunities and limitations associated with thesemousemodelswillbediscussedandthepotentialapplicationofthese models for understanding the regulation of antibodyresponses against factor VIII in hemophilia A will be indi-cated.Keywords: CD4+ Tcells,factorVIIIinhibitors,hemophiliaA,HLA class II, mouse models.Significance of MHC class II molecules for the regulationof immune responses against proteinsMHC class II molecules play an important role in the controlof adaptive immune responses against protein antigens. Theyare essential for shaping the CD4+ T-cell repertoire in thethymusandtheyselecttheantigenicpeptidesthatarepresentedto CD4+ T cells in the periphery [1]. Today, it is generallyacceptedthatBcellsneedthehelpofactivatedCD4+Tcellstodevelop high-affinity antibody responses against protein anti-gens[2,3].CD4+TcellsexpressT-cellreceptorsthatrecognizeantigen-derived peptides which are presented by MHC class IImolecules expressed on specialized antigen-presenting cells inthe periphery [4]. Structural features of both the MHC class IImolecule and the antigenic peptide determine the specificity ofCD4+ T cells that can bind to the complex formed betweenMHC class II molecules and peptides [4–6]. The conditionsunder which CD4+ T cells interact with these complexesdetermine whether the immune system is nonresponsive, isactivated to develop specific antibodies or is tolerized tosuppress antibody development [6,7].MHC-class II molecules are heterodimeric proteins. Theyconsist of two non-covalently associated polypeptide chains,the alpha chain and the beta chain (Fig. 1) [for review see 8].The amino-terminal alpha 1 (a1) and beta 1 (b1) regions of thepolypeptide chains form an open binding groove for peptides.The binding groove presents peptides to CD4+ T cells [forreview see 8]. Crystal structures of complexes between humanMHC class II molecules and peptides have indicated that thepeptide binding grooves of the different MHC class II isotypesare superimposable and that the backbone of peptides boundto the binding grooves is highly conserved [for review see 8].Thebindinggroovesaremainlycharacterizedbythepropertiesof the so-called P1, P4, P6 and P9 pockets (Fig. 1), whichconfer the specificity to the anchor residues of the peptidesboundtothegroove[forreviewsee8].Theconformationofthepeptide (residues 1–9, see Fig. 1) that is bound to the groove isdetermined by hydrogen bonding by MHC class II residues tothe peptide backbone. Therefore, the conformation adoptedby the peptide is independent of its sequence and is differentfromtheconformationofthepeptidesequenceinthecontextofits native protein [8,9].MHC class II molecules bind peptides in endocytic vesiclesof antigen-presenting cells. Peptides bound to MHC class IImolecules are heterogenous in size (usually 12–26 mers). Theyare selected as families consisting of a common binding core(peptides 1–9, see Fig. 1) and varying flanking regions [6]. Theplasticity of peptide- MHC class II interactions permits theformation of multiple conformational isomers by the samepeptideand MHCclass IImolecule[10].These conformationalisomers are determined by the flanking regions of the peptide[10]. Different conformational isomers of the same peptide-MHCclassIIcomplexmightberecognizedbydifferentCD4+T cells [11].The identification of peptides selected by MHC class IImolecules during natural processing of factor VIII (FVIII) will