No abstract

No abstract

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.

StlmmaryDuring thymic maturation, CD4-CD8-TCR-immature thymocytes differentiate through a CD4+CD8+TCR 1~ 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 an 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 ceils, 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. Mature CD4+CD8 -class II-restricted and CD4-CD8 + class I-restricted lymphocytes differentiate intrathymically from CD4-CD8-TCR-cells that originate from fetal liver or bone marrow precursors (1). The major intermediate in the T cell differentiation pathway is the doublepositive thymocyte, which expresses both CD4 and CD8 and low levels of the od3 TCR. Antibody blocking experiments (2, 3), as well as more recent studies in gene knockout mice (4,5), have demonstrated that CD4 and CD8 are essential for the differentiation of double-positive thymocytes into mature class II-and class I-restricted T cells, respectively. On mature T cells, CD4 and CD8 participate in Ag recognition and T cell activation by binding to monomorphic determinants on MHC class II and class I proteins, respectively (6-12). Coengagement of an Ag-MHC complex by an c~/3 TCR and either CD4 or CD8 is believed to be a critical component of the T cell activation pathway (13-17). The lymphocytespecific tyrosine kinase, p56 lck, is physically associated with the cytoplasmic domains of both CD4 and CD8 and can be activated by antibody crosslinking of either of these glycoproteins (18-21). Thus, coengagement of Ag-MHC by the TCR and CD4 or CD8 may trigger T cell activation by transducing transmembrane signals via p56 lck (22,23). By binding MHC, CD4 and CD8 m...