HLA class II transgenic mice: models of the human CD4⁺ T‐cell immune response

Abstract

This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA-DR4 transgenic lines with normally expressed HLA-DR4 molecules have been produced. To obtain adequate positive selection of the HLA-DR4-restricted CD4+ T-cell repertoire in these mice it is essential both to introduce a human CD4 transgene, and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA-DR4 transgenic mice have been used to determine the immunogenic CD4+ T-cell epitopes of several human autoantigenic proteins.

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

“…A number of HLA-transgenic mouse models have been developed to study autoimmunity, and these have proven valuable in evaluating the role of individual HLA genes in disease susceptibility (8,9,(53)(54)(55). However, there are no HLA-transgenic mouse models that express multiple linked genes from common autoimmuneprone human haplotypes.…”

“…The mechanism by which particular haplotypes such as HLA DR3-DQ2 are associated with different autoimmune disorders is not known. Transgenic models have so far relied on single gene transgenic mice (8,9) or have recreated haplotype combinations by breeding mice to express multiple genes in trans (6,11,13). This approach has several drawbacks.…”

“…Autoimmune diseases such as type 1 insulin-dependent diabetes mellitus (IDDM) 3 and systemic lupus erythematosus are strongly associated with particular HLA class II alleles (2,3) or with combinations of alleles either in cis (haplotypes) (4) or in trans (4 -6). Although population data (7) and studies of transgenic mice (8,9) have identified some of the individual genes that are responsible for disease susceptibility in MHC haplotypes, some studies conclude that disease risk is conferred by combinations of HLA DR and DQ genes (6, 10 -13) and may involve genes within the class III region of the MHC (12,14). This has led to suggestions that disease susceptibility may depend upon the MHC haplotype context rather than any particular gene within the haplotype (4,6).…”

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

“…Studies suggest that the peptides are loaded onto class II proteins in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5,[8][9][10]. Processed peptides can also bind to mature class II molecules on the surface of APC for direct presentation to CD4 + T cells.…”

“…Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur.…”