Reciprocal transfer of class I MHC allele specificity between activating Ly-49P and Ly-49W receptors by exchange of beta 4-beta 5 loop residues.
Receptors of the Ly-49 multigene family regulate rodent NK cell functions. Ly-49Rs are highly polymorphic and exist in either activating or inhibitory forms. Examples of both Ly-49 receptor types have been shown to recognize class I MHC ligands. Ly-49Rs can distinguish between class I alleles, but the molecular basis of this discrimination is unknown. Two activating receptors, Ly-49P and Ly-49W, differ in class I recognition, recognizing H-2D(d), or H-2D(d) and D(k), respectively. In this report, we demonstrate that specificity for H-2D(k) can be transferred from Ly-49W to Ly-49P by substituting 3 aa predicted to reside in the beta4-beta5 loop of Ly-49W into Ly-49P. Replacement of these same residues of Ly-49W with corresponding residues in Ly-49P eliminates H-2D(k) recognition while still preserving H-2D(d) recognition. Further mutagenesis indicates that all 3 aa facilitate optimal class I specificity exchange. These results provide the first evidence for a specific site on Ly-49Rs, the beta4-beta5 loop, in determining class I MHC allele specificity.
Ma
Brian J
BJ
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
Silver
Elizabeth T
ET
Hazes
Bart
B
Kane
Kevin P
KP
D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001224:Aspartic Acid / Q000235:genetics; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics* / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary / Q000235:genetics; D051381:Rats; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D000950:Antigens, Ly; D000939:Epitopes; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; C423703:Ly-49W receptor; C400050:Ly49P receptor; D011971:Receptors, Immunologic; D001224:Aspartic Acid; D005998:Glycine