Major Histocompatibility Complex 2016; 23 (2): 80 95 28 HLA HLA 1)2) 1)2) 1)2) 1) 2) HLA T HLA X HLA HLA I HLA HLA KIR LILR NKG2/CD94 X 1 major histocompatibility complex: MHC human leukocyte antigen: HLA HLA HLA HLA 6 X HLA HLA I II HLA T HLA I T HLA I II HLA I X 2016 6 28 2016 6 28 060 0812 12 6 TEL: 011 706 3970 FAX: 011 706 4986 E-mail: maenaka@pharm.hokudai.ac.jp 80
HLA MHC 2016; 23 (2) 2 HLA 1 HLA I HLA I 8-11 T I T HLA I HLA-A B C HLA I I I I I I HLA I 3 α1 α2 α3 1 β2 β2m 1 β2m 15 MHC HLA I α3 HLA I α1 α2 8 β 2 α 1B HLA I β2m HLA I free heavy chain:fhc fhc CD8 TCR/CD3 MHCI MHCII 1) 2 HLA II HLA II HLA-DR DQ DP B T HLA II 2 α α1 α2 β β1 β2 α β α1 β1 I 2 2) I I II α β 1A 2A II 図 1 HLA I A HLA I B HLA-A2 PDB ID: 2BCK β2m 81
MHC 2016; 23 (2) HLA 図 2 HLA II A HLA II B HLA-DR PDB ID: 3C5J α β 3 HLA HLA I II 1 2 HLA I II 3 I 8 11 II 10 30 II B 3) II HLA I I transporter associated with antigen processing TAP I 図 3 HLA I II HLA-A2 HLA-DR HLA N 8 16 I 1 endoplasmic reticulum aminopeptidase 1 ERAP1 HLA I HLA-B27 ERAP1 4) HLA-B51 5) I I HLA-B27 N 2 P2 82
HLA MHC 2016; 23 (2) Arg 4 I HLA 4B HLA I X HLA-B*5701 T 6) HLA HLA II II II II class II-associated invariant-chain peptides CLIP II I II 5C II I II 3 HLA T 1 HLA I T T T cell receptor: TCR MHC I α1-α2 MHC I 図 4 HLA-B27 A HLA-B27/HIV KRWIILGLNK PDB ID: 2BSS HLA-B27 N P1-P10 B HLA-B27 P2 Arg C PDB ID 83
MHC 2016; 23 (2) HLA 図 5 HLA I II TCR A HLA I TCR PDB ID: 2VLR B HLA II TCR PDB ID: 1FYT C B IIβ TCR TCR HLA 1 2 TCR α β 5A I TCR HLA T I MHC I TCR Human immunodeficiency virus HIV 2 HLA II HLA II T HLA II T T HLA II 5B, C CLIP HLA-DR1 P1 C 7) TCR 4 HLA I HLA I HLA-A B C I I 1 1 HLA-E HLA-E I HLA-E 10 HLA-E*0101 HLA-E*0103 2 50% 1 Arg107Gly 2 8) HLA-E HLA I I 84
HLA MHC 2016; 23 (2) 1 I I HLA-E HLA I NKG2/CD94 HLA-F LILR? HLA-G LILRB1 LILRB2 LILRA3 KIR2DL4 CD1a 1b 1c T TCR CD1d NKT TCR CD1e MICA MICB NKG2D HLA-E NKG2/CD94 HLA-E I HLA-E I P2 P3 P6 P7 P9 2 HLA-G HLA-G HLA I HLA-G T HLA-G HLA-G I HLA-G1 G7 Cys42 HLA-G1 HLA-G5 HLA-G1 Cys42 N Asn86 9) in vivo 9,10) α2 HLA-G2 HLA-G6 HLA-G1 11) HLA-G 3 CD1 CD1 HLA I 6 CD1 CD1a, 1b, 1c, 1d 1e 5 3 I CD1a, 1b, 1c II CD1d III CD1e I, II CD1 CD1e CD1e CD1 I CD1 CD1 NKT γδ T IFN-γ IL-4 NKT I NKT II NKT I NKT TCR α Vα24Jα18 β Vβ11 invariant NKT inkt semi-invariant NKT 6 I NKT α- αgalcer αgalcer α 18 26 6 αgalcer II NKT CD1d I NKT TCR αgalcer II NKT 1 7 CD1 85
MHC 2016; 23 (2) HLA 図 6 HLA I HLA II CD1d HLA I CD8 T HLA II CD4 T CD1d inkt HLA I HLA II TCR T CD1d inkt TCR inkt inkt inkt CD1 T 1 Mycobacterium tuberculosis I CD1 CD1a, 1b, 1c 7 inkt T inkt αgalcer α- α inkt NKT CD1a, 1b, 1c T CD1 MHC I α1, α2, α3 β2m α1-α2 MHC I 7 CD1 A F MHC A F 7 2 CD1b A F C T CD1 F F CD1b CD1c 86
HLA MHC 2016; 23 (2) 図 7 CD1d HLA-A2 A. CD1d PDB ID: 1ZT4 α1 α2 CD1d β2m αgalcer B. HLA-A2 PDB ID: 1DUZ α1 α2 HLA-A2 β2m C. A αgalcer D. CD1 C D C D TCR CD1 TCR CD1 TCR 8 I NKT TCR V α24-vβ11 CD1d II NKT TCR Vα1Jα26-Vβ16Jβ2.1 CD1d TCR HLA TCR TCR MHC MHC α1, α2 I NKT TCR TCR α β CD1d α1, α2 F CDR1α αgalcer CDR3α CD1d αgalcer CDR2β Tyr48, Tyr50 CD1d F II NKT TCR TCR α β CD1d α1, α2 A TCR CDR3α CD1d CDR3β αgalcer II NKT TCR II NKT TCR 5 HLA I 1 HLA I HLA I 87
MHC 2016; 23 (2) HLA の立体構造と免疫制御受容体の分子認識機構 図8 TCR-HLA 複合体と TCR-CD1d 複合体の比較 A. TCR と HLA-A2 複合体の結晶構造 PDB ID: 5D2L TCR HLA-A2 と β2m をリボンモデル ペプチドをスティックモデルで示した B. I 型 NKT 細胞の TCR と CD1d 複合体の結晶構造 PDB ID: 2PO6 TCR CD1d と β2m をリボンモデル αgalcer をスティックモデ ルで示した C. II 型 NKT 細胞の TCR と CD1d 複合体の結晶構造 PDB ID: 4EI5 TCR CD1d と β2m をリボンモデル スルファチドをスティッ クモデルで示した 細胞受容体がどのように認識し 免疫反応制御を行って 構造やクラス I に対する結合様式 特異性が異なってお いるのか HLA クラス I と受容体の複合体構造解析に り HLA クラス I が多種の受容体を用いて多面的に免 より明らかとなってきた HLA クラス I 受容体としては 疫制御を行っていることがうかがえる TCR CD8 に加え ペア型受容体に属する killer cell im- KIR LILR および CD94/NKG2 は いずれも相同性の munoglobulin-like receptor KIR および leukocyte immu- 高いリガンド結合部位を含む細胞外ドメインを持つが noglobulin-like receptor LILR CD94/NKG2 ファミリー 抑制性受容体と活性化受容体がそれぞれペアで存在する が報告されている 表 2 それぞれの受容体は自身の ペア型受容体である 88 12) 抑制性受容体は細胞内に immu-
HLA MHC 2016; 23 (2) 表 2 HLA I KIR2DL1 2 HLA-C KIR2DL2 1 HLA-C 2 HLA-C HLA-B KIR2DL3 1 HLA-C 2 HLA-C HLA-B KIR2DL4 HLA-G KIR2DL5 KIR3DL1 HLA-Bw4 HLA-A KIR3DL2 HLA-A3 A11 CpG ODN KIR3DL3 KIR2DS1 2 HLA-C KIR2DS2 HLA-A11 1 HLA-C KIR2DS3 2 HLA-C KIR2DS4 HLA-Cw4 A11 KIR2DS5 KIR3DS1 HLA-Bw4 HLA-A LILRB1 HLA-A B C E F UL18 CD94/NKG2A HLA-E CD94/NKG2C HLA-E CD94/NKG2E HLA-E NKG2D/NKG2D MICA MICB ULBP noreceptor tyrosine-based inhibitory motif ITIM Arg Lys immunoreceptor tyrosine-based activation motif ITAM HLA I I 2 2 KIR KIR KIR NK T Ig D0 D1 D2 2 KIR2D 3 KIR3D short S long L 9 HLA I KIR2DL KIR3DL ITIM KIR2DS KIR3DS Lys ITAM DNAX activating protein of 12 kda DAP12 KIR KIR2DL1 KIR2DS1 D1D2 5 KIR2D HLA KIR2D 2 β D1 D2 10A HLA 2 X KIR2D HLA-C HLA-C 2 77 Ser 80 Asn 1 HLA-C Cw1 Cw3 Cw7 Cw8 Cw12 Cw13 Cw14 KIR2DL2 2DL3 KIR2DS2 77 Asn 80 Lys 2 89
MHC 2016; 23 (2) HLA 図 9 KIR KIR2D D1-D2 D0-D2 ITIM KIR ITAM KIR KIR2DL4 ITIM ITAM FcRγ KIR2DL4 HLA-G A KIR2DL1 PDB ID: 2VLR B LILRB1 D1D2 PDB ID: 1G0X B LILRB2 D1D2 PDB ID: 2GW5 図 10 HLA I HLA-C Cw2 Cw4 Cw5 Cw6 Cw15 Cw17 Cw18 KIR2DL1 KIR2DS1 2 HLA-Cw3 1 /KIR2DL2 HLA-Cw4 2 /KIR2DL1 KIR HLA-C α1-α2 7 8 11A HLA-C 80 KIR D1 44 KIR 44 Lys KIR2DL2 1 HLA-Cw3 Asn80 11B 44 Met KIR2DL1 HLA-Cw4 HLA-Cw4 Lys80 Lys80 KIR2DL1 Met44 Ser184 Glu187 11C KIR2DL1 Met44 Lys Lys HLA-Cw4 Lys80 HLA-Cw4 KIR KIR KIR2DL3 3 90
HLA MHC 2016; 23 (2) 図 11 KIR HLA I A KIR2DL1 HLA-Cw4 PDB ID: 1IM9 C B HLA-Cw3/KIR2DL2 1EFX HLA-Cw3 Asn80 KIR2DL2 Lys44 C HLA-Cw4/KIR2DL1 1IM9 HLA-Cw4 Lys80 KIR2DL1 Met44 Lys80 KIR2DL1 Ser184 Glu187 D KIR3DL1 HLA-B*5701 PDB ID: 3VH8 KIR2D KIR3DL1 HLA-Cw7 KYFDEHYEY RYRPGTVAL K d =6.9 μm NKADVILKY K d =115 μm MHCI / KIR2DS2 HLA-A11 KIR2D HLA-C KIR-HLA KIR3D HLA KIR3D HLA-A HLA-B 2 X KIR3DL1D1 HLA-B C KIR3D D0 11D KIR3DL2 HLA I CpG oligodeoxynucleotide ODN TLR9 NK KIR HLA I KIR 2 KIR KIR/HLA I KIR HLA I KIR/HLA I 13 15) KIR HLA KIR KIR MHC KIR HLA I 16,17) 3 LILR LILR 11 LILRB1-5 LILRA1 2 4-6 LILRA3 91
MHC 2016; 23 (2) LILRB1 B2 I I 2 KIR LILR KIR LILR 4 N D1D2 KIR2DL 2 10B, C KIR LILR HLA I LILRB1/HLA-A2 LILRB2/ HLA-G LILR B1 B2 D1-D2 β2m D1 α3 TCR KIR 12 LILR α3 β2m MHC I HLA TCR KIR KIR LILR 18) I T CD8 HLA I 18) LILRB1 B2 ITIM CD8 HLA I T in vivo T 19) LILRB1 B2 HLA I LILRB1 LILRB2 HLA-G HLA-G LILR LILRB1 HCMV HLA I UL18 LILRB1/UL18 HLA 図 12 LILRB1 HLA-A2 PDB ID: 1P7Q TCR KIR HLA I α3 β2m 2 LILRB1 LILRB1 HLA I UL18 α3 β2m α3 HLA I 1000 UL18 TCR KIR CD8 LILRB1 4 CD94/NKG2 HLA I HLA-E NK HLA-E HLA 9 5 Arg 8 HLA-E NK NKG2 CD94 NKG2 CD94 C NKG2 7 NKG2A, B, C, D, E, F, H NKG2 NK 13 CD94 / NKG2 NKG2C NKG2E NKG2H 92
HLA MHC 2016; 23 (2) 図 13 CD94/NKG2 CD94/NKG2 HLA-E NKG2C DAP12 NKG2A ITIM ITAM DAP12 NKG2A NKG2B ITIM NKG2D HLA-E NKG2A/CD94 NKG2C/CD94 HLA-E 6 NKG2 HLA-E NKG2A/CD94 HLA-G VMAPRTLFL HLA-E PDB IDs: 3CII and 3CDG 14 α1-α2 NKG2A CD94 HLA-E α1-α2 P5 Arg P8 Phe NKG2A/CD94 Arg Phe CD94 HLA-E NKG2A/CD94 CD94 NKG2A/CD94 HLA-E CD94 HLA-E 6 NKG2A/CD94 NKG2C/ CD94 NKG2 CD94 P5 Arg HLA-E 図 14 CD94/NKG2A HLA-G VMAPRTLFL HLA-E PDB ID: 3CDG HLA-E α1-α2 P5 Arg P8 Phe CD94/NKG2A 6 HLA TCR HLA-KIR HLA I HLA 1) Arosa FA, Santos SG, and Powis SJ: Open conformers: the hidden face of MHC-I molecules. Trends Immunol (28): 115 123, 2007. 2) Dai S, Crawford F, Marrack P, et al.: The structure of HLA- DR52c: comparison to other HLA-DRB3 alleles. Proceedings of the National Academy of Sciences of the United States of America (105): 11893 11897, 2008. 3) Jin H, Arase N, Hirayasu K, et al.: Autoantibodies to IgG/HLA class II complexes are associated with rheumatoid arthritis susceptibility. Proceedings of the National Academy of Sciences of the United States of America (111): 3787 3792, 2014. 93
MHC 2016; 23 (2) 4) Keidel S, Chen L, Pointon J, et al.: ERAP1 and ankylosing spondylitis. Curr Opin Immunol (25): 97 102, 2013. 5) Kirino Y, Bertsias G, Ishigatsubo Y, et al.: Genome-wide association analysis identifies new susceptibility loci for Behcet s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet (45): 202 207, 2013. 6) Chessman D, Kostenko L, Lethborg T, et al.: Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity (28): 822 832, 2008. 7) Gunther S, Schlundt A, Sticht J, et al.: Bidirectional binding of invariant chain peptides to an MHC class II molecule. Proceedings of the National Academy of Sciences of the United States of America (107): 22219 22224, 2010. 8) Iwaszko M, and Bogunia-Kubik K: Clinical significance of the HLA-E and CD94/NKG2 interaction. Arch Immunol Ther Exp (Warsz) (59): 353 367, 2011. 9) Shiroishi M, Kuroki K, Ose T, et al.: Efficient leukocyte Ig-like receptor signaling and crystal structure of disulfide-linked HLA- G dimer. The Journal of biological chemistry (281): 10439 10447, 2006. 10) Kuroki K, Hirose K, Okabe Y, et al.: The long-term immunosuppressive effects of disulfide-linked HLA-G dimer in mice with collagen-induced arthritis. Human immunology (74): 433 438, 2013. 11) Takahashi A, Kuroki K, Okabe Y, et al.: The immunosuppressive effect of domain-deleted dimer of HLA-G2 isoform in collageninduced arthritis mice. Human immunology 2016. 12) Kuroki K, Furukawa A, and Maenaka K: Molecular recognition of paired receptors in the immune system. Frontiers in microbiol- HLA ogy (3): 429, 2012. 13) Williams AP, Bateman AR, and Khakoo SI: Hanging in the balance. KIR and their role in disease. Mol Interv (5): 226 240, 2005. 14) Parham P: MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol (5): 201 214, 2005. 15) Carrington M, and Martin MP: The impact of variation at the KIR gene cluster on human disease. Curr Top Microbiol Immunol (298): 225 257, 2006. 16) Hong HA, Loubser AS, de Assis Rosa D, et al.: Killer-cell immunoglobulin-like receptor genotyping and HLA killer-cell immunoglobulin-like receptor-ligand identification by real-time polymerase chain reaction. Tissue Antigens (78): 185 194, 2011. 17) Bari R, Leung M, Turner VE, et al.: Molecular determinantbased typing of KIR alleles and KIR ligands. Clin Immunol (138): 274 281, 2011. 18) Shiroishi M, Tsumoto K, Amano K, et al.: Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proceedings of the National Academy of Sciences of the United States of America (100): 8856 8861, 2003. 19) Liang S, Zhang W, and Horuzsko A: Human ILT2 receptor associates with murine MHC class I molecules in vivo and impairs T cell function. European journal of immunology (36): 2457 2471, 2006. 2 94
HLA MHC 2016; 23 (2) Structures and receptor recognition mechanism of HLA molecules Kimiko Kuroki 1)2), Shunsuke Kita 1)2), Katsumi Maenaka 1)2) 1) Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University. 2) Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University. Human Leukocyte Antigens (HLAs) are glycoproteins that exhibit unusually high genetic polymorphism as well as high polygenecity by forming a wide variety of gene families. HLAs generally display peptides derived from intracellular proteins to T cells, and furthermore, they interact with various immune cell surface receptors to control broad aspects of immune responses pleiotropically, resulting in the maintenance of homeostasis in our body. X-ray crystallography has remarkably contributed to understanding of precise mechanisms for these HLA interactions. In this issue, we describe molecular structures of HLAs and HLA-receptor complexes, showing how HLA molecules regulate immune responses, and further discuss about their relationship with diseases. Key Words: killer cell Ig-like receptors, leukocyte Ig-like receptors, X-ray crystallography, nonclassical HLA, CD94/NKG2 receptors 2016 95