A 2ND LINEAGE OF MAMMALIAN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I GENES

Major histocompatibility complex (MHC) class I genes typically encode polymorphic peptide-binding chains which are ubiquitously expressed an d mediate the recognition of intracellular antigens by cytotoxic T cel ls. They constitute diverse gene families in different species and inc lude the numerous so-called nonclassical genes in the mouse H-2 comple x, of which some have been adapted to variously modified functions. We have identified a distinct family of five related sequences in the hu man MHC which are distantly homologous to class I chains. These MIC ge nes (MHC class I chain related genes) evolved in parallel with the hum an class I genes and with those of most if not all mammalian orders. T he MICA gene in this family is located near HLA-B and is by far the mo st divergent mammalian MHC class I gene known. It is further distingui shed by its unusual exon-intron organization and preferential expressi on in fibroblasts and epithelial cells. However, the presence of diagn ostic residues in the MICA amino acid sequence translated from cDNA su ggests that the putative MICA chain folds similarly to typical class I chains and may have the capacity to bind peptide or other short ligan ds. These results define a second lineage of evolutionarily conserved MHC class I genes. This implies that MICA and possibly other members i n this family have been selected for specialized functions that are ei ther ancient or derived from those of typical MHC class I genes, in an alogy to some of the nonclassical mouse H-2 genes.