Human leukocyte antigen F (HLA-F). An expressed HLA gene composed of a class I coding sequence linked to a novel transcribed repetitive element.

Abstract

We describe here the isolation and sequencing of a previously uncharacterized HLA class I gene. This gene, HLA-5.4, is the third non-HLA-A,B,C gene characterized whose sequence shows it encodes an intact class I protein. RNase protection assays with a probe specific for this gene demonstrated its expression in B lymphoblastoid cell lines, in resting T cells, and skin cells, while no mRNA could be detected in the T cell line Molt 4. Consistent with a pattern of expression different from that of other class I genes, DNA sequence comparisons identified potential regulator motifs unique to HLA-5.4 and possibly essential for tissue-specific expression. Protein sequence analysis of human and murine class I antigens has identified 10 highly conserved residues believed to be involved in antigen binding. Five of these are altered in HLA-5.4, and of these, three are nonconservative. In addition, examination of the HLA-5.4 DNA sequence predicts that the cytoplasmic segment of this protein is shorter than that of the classical transplantation antigens. The 3' untranslated region of the HLA-5.4 gene contains one member of a previously undescribed multigene family consisting of at least 30 members. Northern analysis showed that several of these sequences were transcribed, and the most ubiquitous transcript, a 600-nucleotide polyadenylated mRNA, was found in all tissues and cells examined. This sequence is conserved in the mouse genome, where a similar number of copies were found, and one of these sequences was also transcribed, yielding a 600-nucleotide mRNA. The characterization of this unique HLA class I gene and the demonstration of its tissue-specific expression have prompted us to propose that HLA-5.4 be designated HLA-F.

Protein Expression and Peptide Binding Suggest Unique and Interacting Functional Roles for HLA-E, F, and G in Maternal-Placental Immune Recognition

“…Although it is not yet clear what role HLA-F plays in the immune response, it has long been reported that the gene is differentially expressed in immune cells (11). Protein expression has been detected in several cell types, although no surface expression has been reported (13,15).…”

“…The m.w. of HLA-F is smaller than other class I because of the absence of exon 7 in the mature transcript (11), and thus HLA-F could be distinguished by m.w. as well.…”

“…A second nonclassical class I protein, HLA-E, is surface expressed on all cells and tissues that express classical class I and on transfectants that express HLA-G (9), and expression on placental cells has been implicated indirectly (10), whereas a definitive examination of cellular distribution in the placenta remains to be completed. HLA-F, the third human nonclassical class I protein (11), has been detected intracellularly in a number of cell lines, but surface expression appeared to be lacking (12,13). HLA-F protein expression in normal tissue has been little examined, and no studies of expression in placental tissue have been reported.…”

Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.

“…The gene responsible for HH has been located on the short arm of chromosome 6, in linkage desequilibrium with the HLA-A locus (8,58), where several nonclassical MHC-I genes have been identified (59)(60)(61). While this paper was under submission, a novel MHC class I-like gene, termed HLA-H, was reported to be mutated in a large majority of HH patients (62).…”

Antibodies to HLA-E in Nonalloimmunized Males: Pattern of HLA-Ia Reactivity of Anti–HLA-E–Positive Sera

“…HLA-E, one of the nonclassical HLA-Ib molecules discovered in 1987 (1)(2)(3), is uniquely distributed on several cells, predominantly endothelial cells, immune cells (B, T lymphocytes, NK cells, monocyte, and macrophages), trophoblasts, and some tumor cells, including melanoma (32)(33)(34). Increased cellular expression of HLA-E results in the release of HLA-E in the circulation (32).…”