Identification of allelic variants of the bovine immune regulatory molecule CEACAM1 implies a pathogen-driven evolution.
Carcinoembryonic antigen-related cell adhesion molecule (CEACAM1), the primordial member of the carcinoembryonic antigen (CEA) family, functions as a MHC-independent natural killer (NK) cell inhibitory receptor, regulates T and B cell proliferation, and induces dendritic cell (DC) maturation. Despite these fundamental functions, CEACAM1 and most of the CEA family members differ significantly in primates and rodents. A number of diverse murine and human pathogens use CEACAM1 as a cellular receptor, indicating that the observed species-specific differences are the result of divergent molecular pathogen/host coevolution. To gain deeper insight into its evolution and function, we cloned CEACAM1 cDNA from cattle as a representative of a third mammalian order. Bovine CEACAM1 differs considerably from rodent and primate CEACAM1 due to deletion of the B domain exon which was most likely caused by insertion of LINE/SINE sequences and reveals alternative splicing within the transmembrane exon. However, the characteristic long and short isoforms exist which contain or lack the typical immunoreceptor tyrosine-based inhibitory motifs (ITIM) in their cytoplasmic tails, respectively. Bovine peripheral blood lymphocytes (PBL) express only ITIM-containing CEACAM1 isoforms, and upregulate their expression upon stimulation, suggesting an inhibitory function in these cells. As found in rodents, two clearly distinct CEACAM1 alleles exist in cattle. In the a allele, a unique deletion of three amino acids is found in the N domain, which is important for pathogen binding in mice and humans. This is consistent with the notion that CEACAM1 serves or has served as a pathogen receptor in cattle.
Kammerer
Robert
R
Tumor Immunology Laboratory, Department of Urology, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 23, Munich D-81377, Germany. robert.kammerer@med.uni-muenchen.de
Popp
Tanja
T
Singer
Bernhard B
BB
Schlender
Jörg
J
Zimmermann
Wolfgang
W
D000483:Alleles; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002272:Carcinoembryonic Antigen; D002417:Cattle / Q000235:genetics* / Q000382:microbiology; D002418:Cattle Diseases / Q000235:genetics / Q000382:microbiology; D015815:Cell Adhesion Molecules; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010802:Phylogeny; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D000596:Amino Acids; D015703:Antigens, CD; D000943:Antigens, Differentiation; C069847:CD66 antigens; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; D020033:Protein Isoforms; D012333:RNA, Messenger