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The T4 molecule may serve as a T-cell receptor recognizing molecules on the surface of specific target cells and also serves as the receptor for the human immunodeficiency virus. To define the mechanisms of interaction of T4 with the surface of antigen-presenting cells as well as with human immunodeficiency virus, we have further analyzed the sequence, structure, and expression of the human and mouse T4 genes. T4 consists of an extracellular segment comprised of a leader sequence followed by four tandem variable-joining (VJ)-like domains, a transmembrane domain, and a cytoplasmic segment. The structural domains of the T4 protein deduced from amino acid sequence are precisely reflected in the intron-exon organization of the gene. Analysis of the expression of the T4 gene indicates that T4 RNA is expressed not only in T lymphocytes, but in B cells, macrophages, and granulocytes. T4 is also expressed in a developmentally regulated manner in specific regions of the brain. It is, therefore, possible that T4 plays a more general role in mediating cell recognition events that are not restricted to the cellular immune response.Analysis of the surface glycoproteins of peripheral T lymphocytes demonstrates that mature T cells segregate into one of two classes: those that express the surface glycoprotein T4 (CD4) and those that express the glycoprotein T8 (CD8) (1). The T4 molecule is primarily expressed on helper T lymphocytes, whereas T8 is expressed on cytotoxic and suppressor T cells (2, 3). T8+ T lymphocytes interact with a broad set of target cells that express class I major histocompatibility complex (MHC) gene products whereas T4+ T cells interact with a more restricted subset of targets, largely macrophages and B cells, that express class II MHC molecules (2, 3). This has led to the suggestion that the specificity of interaction of subpopulations of T lymphocytes with various target cells results in part from the association of T4 and T8 with the products of different MHC genes. T4 may not only serve as a receptor recognizing molecules on the surface of target cells, but also serves as the receptor for the human immunodeficiency virus (HIV) (4-7).We have isolated (8) the cDNA and the gene encoding T4 and have determined the nucleotide sequence of the fulllength cDNA clone. To define the mechanisms of interaction of T4 with the surface of both antigen-presenting cells as well as with HIV, we have further analyzed the sequence, structure, and expression of the human and mouse § T4 genes. Human T4, as well the mouse homologue L3T4, exhibit a polyimmunoglobulin-like structure with four tandem variable-joining (VJ)-like domains. This polyimmunoglobulinlike structure of T4 is homologous to an increasingly large number of recognition molecules. Moreover, we observe that T4 expression is not restricted to T cells, suggesting that T4 plays a more general role in cell-cell interactions. MATERIALS AND METHODSAll materials and procedures have been described (7-9). RESULTS T4 Exhibits a Polyimmunoglobulin-like Structur...