Although Divergent in Residues of the Peptide Binding Site, Conserved Chimpanzee Patr-AL and Polymorphic Human HLA-A*02 Have Overlapping This information is current as Peptide-Binding Repertoires of September 26, 2021. Michael Gleimer, Angela R. Wahl, Heather D. Hickman, Laurent Abi-Rached, Paul J. Norman, Lisbeth A. Guethlein, John A. Hammond, Monia Draghi, Erin J. Adams, Sean Juo, Roxana Jalili, Baback Gharizadeh, Mostafa Ronaghi, K. Downloaded from Christopher Garcia, William H. Hildebrand and Peter Parham J Immunol 2011; 186:1575-1588; Prepublished online 5 January 2011; doi: 10.4049/jimmunol.1002990 http://www.jimmunol.org/ http://www.jimmunol.org/content/186/3/1575 Supplementary http://www.jimmunol.org/content/suppl/2011/01/05/jimmunol.100299 Material 0.DC1 References This article cites 87 articles, 24 of which you can access for free at: by guest on September 26, 2021 http://www.jimmunol.org/content/186/3/1575.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Although Divergent in Residues of the Peptide Binding Site, Conserved Chimpanzee Patr-AL and Polymorphic Human HLA-A*02 Have Overlapping Peptide-Binding Repertoires Michael Gleimer,*,† Angela R. Wahl,‡ Heather D. Hickman,‡ Laurent Abi-Rached,† Paul J. Norman,† Lisbeth A. Guethlein,† John A. Hammond,† Monia Draghi,† Erin J. Adams,x Sean Juo,x Roxana Jalili,{ Baback Gharizadeh,{ Mostafa Ronaghi,{ K. Christopher Garcia,x William H. Hildebrand,‡ and Peter Parham† Patr-AL is an expressed, non-polymorphic MHC class I gene carried by ∼50% of chimpanzee MHC haplotypes. Comparing Patr- AL+ and Patr-AL2 haplotypes showed Patr-AL defines a unique 125-kb genomic block flanked by blocks containing classical Patr-A Downloaded from and pseudogene Patr-H. Orthologous to Patr-AL are polymorphic orangutan Popy-A and the 59 part of human pseudogene HLA-Y, carried by ∼10% of HLA haplotypes. Thus, the AL gene alternatively evolved in these closely related species to become classical, nonclassical, and nonfunctional. Although differing by 30 aa substitutions in the peptide-binding a1 and a2 domains, Patr-AL and HLA-A*0201 bind overlapping repertoires of peptides; the overlap being comparable with that between the A*0201 and A*0207 subtypes differing by one substitution. Patr-AL thus has the A02 supertypic peptide-binding specificity. Patr-AL and HLA-A*0201 have similar three-dimensional structures, binding peptides in similar conformation. Although comparable in size and shape, the http://www.jimmunol.org/ B and F specificity pockets of Patr-AL and HLA-A*0201 differ in both their constituent residues and contacts with peptide anchors. Uniquely shared by Patr-AL, HLA-A*0201, and other members of the A02 supertype are the absence of serine at position 9 in the B pocket and the presence of tyrosine at position 116 in the F pocket. Distinguishing Patr-AL from HLA-A*02 is an 2 unusually electropositive upper face on the a2 helix. Stimulating PBMCs from Patr-AL chimpanzees with B cells expressing Patr-AL produced potent alloreactive CD8 T cells with specificity for Patr-AL and no cross-reactivity toward other MHC class I molecules, including HLA-A*02. In contrast, PBMCs from Patr-AL+ chimpanzees are tolerant of Patr-AL. The Journal of Immunology, 2011, 186: 1575–1588. ajor histocompatibility complex class I molecules bind adaptive immunity that defend against intracellular infection and by guest on September 26, 2021 intracellular peptides and transport them to the cell cancer. Because of the strong and varying selection pressures from M surface (1). There they interact with the receptors of viruses and other pathogens, the family of genes encoding MHC NK cells (2) and CD8 T cells (3), lymphocytes of innate and class I molecules is fast-evolving and varies between species (4, 5). Common features of the MHC class I gene family are highly polymorphic genes encoding classical class I molecules, conserved *Graduate Program in Immunology, Stanford University School of Medicine, Stan- genes encoding nonclassical class I molecules, and a variety of class ford, CA 94305; †Department of Structural Biology, Stanford University School of I pseudogenes and gene fragments (6, 7). Polymorphism provides Medicine, Stanford, CA 94305; ‡Department of Microbiology and Immunology, x diversity and change in the peptide-binding repertoire of MHC University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; De- partment of Molecular and Cellular Pharmacology, Howard Hughes Medical Insti- class I molecules, whereas conservation allows consistently valu- { tute, Stanford University School of Medicine, Stanford, CA 94305; and Stanford able functions to be kept and shared by all members of a species. Genome Technology Center, Stanford University School of Medicine, Palo Alto, CA . 94304 Although chimpanzee and human genomes share 95% se- quence similarity (8, 9), chimpanzees are less susceptible to many Received for publication September 7, 2010. Accepted for publication November 30, 2010. human diseases, including malaria, hepatitis B virus, and cancer, This work was supported by National Institutes of Health Grants AI031168 (to P.P.) as well as HIV-1 (10, 11). In this context, any difference between and RO1-AI4840 (to K.C.G.), the Howard Hughes Medical Institute (to K.C.G.), the immune system genes of the two species becomes a potential a Smith Stanford Graduate fellowship and Howard Hughes Medical Institute Pre- candidate for contributing to disease resistance or susceptibility. doctoral fellowship (to M.G.), and Yerkes Center Base Grant RR000165. Humans have six functional MHC class I genes of which HLA-A, The sequences presented in this article have been submitted to GenBank (http://www. ncbi.nlm.nih.gov/Genbank/) under accession numbers HM629932 (Patr-AL haplo- -B, and -C are highly polymorphic and HLA-E,-F, and -G are type), HM629928 (Gogo-A*0501 flanking sequence), HM629929 (Gogo-A*0401 conserved (12, 13). Chimpanzees have orthologues (Patr-A,-B, flanking sequence), HM629930 (HLA-Y flanking sequence), and HM629931 (intron 3 -C, -E, -F, and -G) of all these genes (14, 15), and their protein of Gogo-A*0501). products have similar functional properties to those of their human Address correspondence and reprint requests to Peter Parham, Department of Struc- tural Biology, Fairchild D-157, 299 Campus Drive West, Stanford, CA 94305. E-mail counterparts (16–22). address: [email protected] Distinguishing the chimpanzee MHC is a seventh MHC class I The online version of this article contains supplemental material. gene, Patr-AL, with no obvious human counterpart (23, 24). In Abbreviations used in this article: BAC, bacterial artificial chromosome; ML, max- comparison with the other expressed class I genes, Patr-AL is imum likelihood; MP, maximum parsimony; mya, million years ago; NJ, neighbor- most similar in sequence to Patr-A and HLA-A (hence the name A- joining; RMSD, root mean square deviation. like), from which it is estimated to have diverged .20 million Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 years ago (mya), long before the separation of chimpanzee and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002990 1576 CHIMPANZEE MHC CLASS I THAT BINDS PEPTIDES LIKE HLA-A*02 human ancestors 6–10 mya (23). Whereas the other human and AL2 haplotypes could be retained under neutrality (i.e., in the absence of chimpanzee MHC class I genes are present on all MHC hap- selection to keep both of them in the population) from the time of the lotypes, Patr-AL is present only on ∼50% of chimpanzee MHC human/chimpanzee divergence until present. The simulations recorded the allele-frequency change per generation and stopped when one haplotype haplotypes (23); an even distribution suggestive of a balancing was lost. Forward-time population simulation was performed using selection that maintains MHC haplotypes with and without Patr- simuPOP (33), assuming a generation time of 15 y, Ne = 30,000 (34), AL. Such selection is a general feature of MHC variation (25). As random mating, and starting haplotype frequencies of 50%. The simu- a consequence of this distribution, a majority of chimpanzees have lations were conservative because reduction in population size, generation time, or unequal starting frequencies would increase the probability of Patr-AL, but, importantly, a significant minority does not. Indeed, losing one haplotype, as would selection for one haplotype. the chimpanzee MHC haplotype sequenced by Anzai et al. (15) has Patr-A,-B,-C,-E,-F, and -G, but lacks Patr-AL. Accordingly, Phylogenetic analysis of MHC-A, MHC-H, and the first objective of our investigation was to define the location MHC-A–related gene sequences and environment of the Patr-AL gene in the chimpanzee MHC, MHC-A, MHC-H,andMHC-A–related gene sequences were aligned using thus defining the genes and genomic region that humans have lost. MAFFT (28) and manual correction of the resulting alignments. The aligned In previous analysis, we showed that Patr-AL exhibits modest sequences were then investigated for the presence of recombinant segments polymorphism and in this regard resembles the nonclassical HLA- using a combination of domain-by-domain phylogenetic analyses and re- combination detection methods, as implemented in the recombination de- E,-F, and -G genes (23).