A single amino acid difference within the alpha-2 domain of two naturally occurring equine MHC class I molecules alters the recognition of Gag and Rev epitopes by equine infectious anemia virus-specific CTL.
Although CTL are critical for control of lentiviruses, including equine infectious anemia virus, relatively little is known regarding the MHC class I molecules that present important epitopes to equine infectious anemia virus-specific CTL. The equine class I molecule 7-6 is associated with the equine leukocyte Ag (ELA)-A1 haplotype and presents the Env-RW12 and Gag-GW12 CTL epitopes. Some ELA-A1 target cells present both epitopes, whereas others are not recognized by Gag-GW12-specific CTL, suggesting that the ELA-A1 haplotype comprises functionally distinct alleles. The Rev-QW11 CTL epitope is also ELA-A1-restricted, but the molecule that presents Rev-QW11 is unknown. To determine whether functionally distinct class I molecules present ELA-A1-restricted CTL epitopes, we sequenced and expressed MHC class I genes from three ELA-A1 horses. Two horses had the 7-6 allele, which when expressed, presented Env-RW12, Gag-GW12, and Rev-QW11 to CTL. The other horse had a distinct allele, designated 141, encoding a molecule that differed from 7-6 by a single amino acid within the alpha-2 domain. This substitution did not affect recognition of Env-RW12, but resulted in more efficient recognition of Rev-QW11. Significantly, CTL recognition of Gag-GW12 was abrogated, despite Gag-GW12 binding to 141. Molecular modeling suggested that conformational changes in the 141/Gag-GW12 complex led to a loss of TCR recognition. These results confirmed that the ELA-A1 haplotype is comprised of functionally distinct alleles, and demonstrated for the first time that naturally occurring MHC class I molecules that vary by only a single amino acid can result in significantly different patterns of epitope recognition by lentivirus-specific CTL.
Mealey
Robert H
RH
Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164, USA. rhm@vetmed.wsu.edu
Lee
Jae-Hyung
JH
Leib
Steven R
SR
Littke
Matt H
MH
McGuire
Travis C
TC
D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015683:Gene Products, gag / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015694:Gene Products, rev / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006736:Horses; D004860:Infectious Anemia Virus, Equine / Q000737:chemistry / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015694:Gene Products, rev; D015395:Histocompatibility Antigens Class I