The X box in the DRA promoter of the human histocompatibility complex is required for expression of the DRA gene in B cells. We show that a B-cell factor binds to a sequence that is clearly distinguishable from binding sites for the previously described X box binding nuclear proteins RF-X, NF-X, NF-Xc, NF-S, hXBP, and AP-1. Mutations in the DRA X box that disrupt the binding of this factor result in a lower level of gene expression, as does the presence of Id (a trans-dominant regulatory protein that negatively regulates helix-loop-helix proteins). Furthermore, this factor is recognized by antibodies directed against the helix-loophelix protein Al, a mouse homolog of the immunoglobulin enhancer binding proteins E12/E47, and it binds to sequences in other genes that were previously shown to bind these proteins. By these criteria, this factor is BCF-1.Class II antigens from the major histocompatibility complex are heterodimeric surface glycoproteins that present antigenic peptides to T lymphocytes, thus initiating the immune response (6,14). Congenital defects in their expression result in a severe combined immunodeficiency or agammaglobulinemia (20), and high levels of expression in certain tissues have been correlated with autoimmunity (13). Class II proteins are encoded by a cluster of genes that are coordinately regulated in a tissue-and cell type-specific manner. In humans, high levels of expression are limited to mature B cells and activated T cells. On antigenpresenting cells and some somatic cells, class II determinants are expressed after induction by gamma interferon (IFN--y) (55).The expression of class II genes requires several DNA sequence motifs (termed the Z, X, and Y boxes) that are conserved in all class II promoters (7,12,21,50,52,56,58,59). The contribution of each of these motifs (and their flanking sequences) to B-cell-specific and IFN--y-inducible expression has been determined in the context of a heterologous (thymidine kinase [TK]) promoter (57). The Y box, which binds the ubiquitously expressed NF-Y heterodimer (26), conferred neither IFN--y inducibility nor B-cell specificity upon the TK promoter, and both the Z and X boxes were required for IFN--y inducibility. In contrast, the X box was sufficient for B-cell-specific expression, suggesting that regulatory proteins involved in B-cell-specific expression of class II promoters interact with the X box and its flanking sequences (the extended X box).The extended X box can be divided into three regions (termed the pyrimidine tract, the core X box, and the X2 box [58]) that have been shown to be important in class II expression. The core X box contains the sequence (positions -108 to -95) in the DRA promoter that is highly conserved in all class II genes. Mutations in this sequence invariably result in loss of class II gene expression (50,51,58,60 (51) found that mutations in the X2 box had a deleterious effect on transcription from the Ea and DRA promoters, respectively. Although Tsang et al. found that mutations in the X2 box had no signific...