Human CD4 Transgenic Mice Research Articles

Definition of MHC and T cell receptor contacts in the HLA-DR4restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice.

Rheumatoid arthritis (RA) is an autoimmune disease associated with the HLA-DR4 and DR1 alleles. The target autoantigen(s) in RA is unknown, but type II collagen (CII) is a candidate, and the DR4- and DR1-restricted immunodominant T cell epitope in this protein corresponds to amino acids 261-273 (CII 261-273). We have defined MHC and T cell receptor contacts in CII 261-273 and provide strong evidence that this peptide corresponds to the peptide binding specificity previously found for RA-associated DR molecules. Moreover, we demonstrate that HLA-DR4 and human CD4 transgenic mice homozygous for the I-Abbeta0 mutation are highly susceptible to collagen-induced arthritis and describe the clinical course and histopathological changes in the affected joints.

Specificity of an HLA‐DRB1*0401‐restricted T cell response to type II collagen

A panel of HLA-DRB1*0401-restricted CD4+ mouse T cell hybridomas specific for bovine type II collagen were generated from transgenic mice expressing the human HLA-DRA1*0101/-DRB1*0401 and CD4 molecules. The vast majority recognized a single peptide determinant corresponding to residues 261-273 (CII 261-273). This determinant was rapidly defined by the use of a predictive algorithm for peptide binding to DRB1*0401. CII 261-273 is conserved in bovine and human type II collagen and overlaps with an important I-A q - restricted T cell determinant in mice with collagen-induced arthritis. This study demonstrates how HLA-DR and human CD4-transgenic mice can be used to identify a T cell epitope in a potential or candidate autoantigen.

O389 - Collagen induced arthritis in HLA-DR4/human CD4 transgenic mice lacking mouse MHC class II molecules

O389 - Collagen induced arthritis in HLA-DR4/human CD4 transgenic mice lacking mouse MHC class II molecules

Thymic development in human CD4 transgenic mice. Positive selection occurs after commitment to the CD8 lineage.

Abstract Developing T cells are positively selected on the basis of their recognition of polymorphic MHCs (major histocompatibility molecules). The CD4 and CD8 co-receptors, together with a compatible TCR-alpha beta, bind class II and class I MHC, respectively, delivering a signal that allows T cell maturation to proceed along the appropriate co-receptor lineage. During development, thymocytes first co-express CD4 and CD8 and subsequently commit to a single co-receptor phenotype. Debate exists over the stage at which positive selection occurs. Positive selection may precede or accompany co-receptor lineage commitment or occur subsequent to the acquisition of a single co-receptor phenotype. We developed transgenic (TG) mice expressing human CD4 (huCD4) on T cells. To study differentiation of CD8+ cells, huCD4 TG mice were bred with mice lacking class I MHC (class I-). This enabled us to assess maturation of mCD8+mCD4+huCD4+ thymocytes to mCD8+mCD4-huCD4+ cells after interaction between huCD4 and mclass II MHC. In the absence of huCD4, class I- mice failed to produce mCD8+ cells. However, expression of huCD4 allowed development of mCD8+mCD4-huCD4+ T cells, suggesting that selection of cells precommitted to the mCD8+mCD4- lineage occurred. Importantly, CD8+ T cells were increased in both the thymus and the periphery of huCD4 TG x class I- animals, indicating their intrathymic origin. V beta 14+ CD8+ T cells were also increased, as predicted for positive selection of CD8+ cells bearing class II-reactive TCRs. These data provide evidence that positive selection occurs at a late stage of thymocyte differentiation, after commitment to the CD8 lineage.

Deletion of T lymphocytes in human CD4 transgenic mice induced by HIV-gp120 and gp120-specific antibodies from AIDS patients.

CD4, a T cell receptor for major histocompatibility complex class II antigen, is a key regulator of immunological reactivities. When engaged together with the T cell antigen receptor, CD4 enhances immune reactions, whereas when ligated independently of the antigen receptor CD4 inhibits the activation of T cells or initiates their deletion. CD4 serves also as a receptor for the human immunodeficiency virus (HIV), which binds the receptor with high avidity through its envelope molecule, gp120. Studies in tissue culture have shown that its affinity to CD4 gives the virus opportunities to utilize CD4-mediated signaling and to manipulate immunocytes. We show here in human CD4 transgenic mice that appropriately cross-linked HIV envelope protein causes massive deletion of HIV-reactive T cells in vivo.

Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer.

During thymic maturation, CD4-CD8-TCR- immature thymocytes differentiate through a CD4+CD8+TCRlo intermediate into two functionally distinct mature T cell subsets: helper T cells expressing CD4 and a major histocompatibility complex (MHC) class II-restricted T cell receptor (TCR), and cytotoxic T cells expressing CD8 and and MHC class I-restricted TCR. The mutually exclusive expression of CD4 and CD8 is maintained in the periphery during expansion of these mature T cell subsets. To elucidate the mechanisms controlling CD4 and CD8 expression on differentiating thymocytes and mature peripheral T cells, we have examined the expression of human CD4 gene constructs in the lymphoid tissues of transgenic mice. Our analyses demonstrate that sequences contained within or closely linked to the human CD4 gene are sufficient to reconstitute the appropriate regulation of human CD4 expression on all thymocyte and mature peripheral T cell subsets. Specifically, appropriate developmental regulation was dependent on two sets of sequences, one contained within a 1.3-kb restriction fragment located 6.5 kb upstream of the human CD4 gene, and the other present within or immediately flanking the gene. Nucleotide sequence analysis identified the 1.3-kb restriction fragment as the likely human homologue of an enhancer found 13 kb upstream of the mouse CD4 transcription initiation site. The human CD4 transgenic mice provide a useful system for the identification and characterization of additional sequence elements that participate in human CD4 gene regulation and for the elucidation of regulatory mechanisms governing the developmental program mediating the maturation of the CD4+ and CD8+ peripheral T cell subsets.