6pa1

Structural highlights

Disease

HLAC_HUMAN B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2). Disease susceptibility is associated with variants affecting the gene represented in this entry. Allele C*06:02 presents a melanocyte autoantigen ADAMTSL5 (VRSRRCLRL) to Valpha3S1/Vbeta13S1 TCR on CD8-positive T cells, and may trigger an autoimmune response against melanocytes.^[1]

Function

HLAC_HUMAN Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity (PubMed:11172028, PubMed:20104487, PubMed:20439706, PubMed:20972337, PubMed:24091323, PubMed:28649982, PubMed:29312307). In complex with B2M/beta 2 microglobulin displays a restricted repertoire of self and viral peptides and acts as a dominant ligand for inhibitory and activating killer immunoglobulin receptors (KIRs) expressed on NK cells (PubMed:16141329). In an allogeneic setting, such as during pregnancy, mediates interaction of extravillous trophoblasts with KIR on uterine NK cells and regulate trophoblast invasion necessary for placentation and overall fetal growth (PubMed:20972337, PubMed:24091323). During viral infection, may present viral peptides with low affinity for KIRs, impeding KIR-mediated inhibition through peptide antagonism and favoring lysis of infected cells (PubMed:20439706). Presents a restricted repertoire of viral peptides on antigen-presenting cells for recognition by alpha-beta T cell receptor (TCR) on HLA-C-restricted CD8-positive T cells, guiding antigen-specific T cell immune response to eliminate infected cells, particularly in chronic viral infection settings such as HIV-1 or CMV infection (PubMed:11172028, PubMed:20104487, PubMed:28649982). Both the peptide and the MHC molecule are recognized by TCR, the peptide is responsible for the fine specificity of antigen recognition and MHC residues account for the MHC restriction of T cells (By similarity). Typically presents intracellular peptide antigens of 9 amino acids that arise from cytosolic proteolysis via proteasome. Can bind different peptides containing allele-specific binding motifs, which are mainly defined by anchor residues at position 2 and 9. Preferentially displays peptides having a restricted repertoire of hydrophobic or aromatic amino acids (Phe, Ile, Leu, Met, Val and Tyr) at the C-terminal anchor (PubMed:25311805, PubMed:8265661).[UniProtKB:P04439]^{[2] [3] [4] [5] [6] [7] [8] [9] [10] [11]} ALLELE C*01:02: The peptide-bound form interacts with KIR2DL2 and KIR2DL3 inhibitory receptors on NK cells. The low affinity peptides compete with the high affinity peptides impeding KIR-mediated inhibition and favoring lysis of infected cells (PubMed:20439706). Presents to CD8-positive T cells a CMV epitope derived from UL83/pp65 (RCPEMISVL), an immediate-early antigen necessary for initiating viral replication (PubMed:12947002).^{[12] [13]} ALLELE C*04:01: Presents a conserved HIV-1 epitope derived from env (SFNCGGEFF) to memory CD8-positive T cells, eliciting very strong IFNG responses (PubMed:20104487). Presents CMV epitope derived from UL83/pp65 (QYDPVAALF) to CD8-positive T cells, triggering T cell cytotoxic response (PubMed:12947002).^{[14] [15]} ALLELE C*05:01: Presents HIV-1 epitope derived from rev (SAEPVPLQL) to CD8-positive T cells, triggering T cell cytotoxic response.^[16] ALLELE C*06:02: In trophoblasts, interacts with KIR2DS2 on uterine NK cells and triggers NK cell activation, including secretion of cytokines such as GMCSF that enhances trophoblast migration.^[17] ALLELE C*07:02: Plays an important role in the control of chronic CMV infection. Presents immunodominant CMV epitopes derived from IE1 (LSEFCRVL and CRVLCCYVL) and UL28 (FRCPRRFCF), both antigens synthesized during immediate-early period of viral replication. Elicits a strong anti-viral CD8-positive T cell immune response that increases markedly with age.^[18] ALLELE C*08:01: Presents viral epitopes derived from CMV UL83 (VVCAHELVC) and IAV M1 (GILGFVFTL), triggering CD8-positive T cell cytotoxic response.^{[19] [20]} ALLELE C*12:02: Presents CMV epitope derived from UL83 (VAFTSHEHF) to CD8-positive T cells.^[21] ALLELE C*15:02: Presents CMV epitope derived from UL83 CC (VVCAHELVC) to CD8-positive T cells, triggering T cell cytotoxic response.^[22]

See Also

• Beta-2 microglobulin 3D structures
• MHC 3D structures
• MHC I 3D structures
• NK cell receptor

References

1. ↑ Arakawa A, Siewert K, Stöhr J, Besgen P, Kim SM, Rühl G, Nickel J, Vollmer S, Thomas P, Krebs S, Pinkert S, Spannagl M, Held K, Kammerbauer C, Besch R, Dornmair K, Prinz JC. Melanocyte antigen triggers autoimmunity in human psoriasis. J Exp Med. 2015 Dec 14;212(13):2203-12. PMID:26621454 doi:10.1084/jem.20151093
2. ↑ Addo MM, Altfeld M, Rosenberg ES, Eldridge RL, Philips MN, Habeeb K, Khatri A, Brander C, Robbins GK, Mazzara GP, Goulder PJ, Walker BD. The HIV-1 regulatory proteins Tat and Rev are frequently targeted by cytotoxic T lymphocytes derived from HIV-1-infected individuals. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1781-6. PMID:11172028 doi:10.1073/pnas.98.4.1781
3. ↑ Stewart CA, Laugier-Anfossi F, Vély F, Saulquin X, Riedmuller J, Tisserant A, Gauthier L, Romagné F, Ferracci G, Arosa FA, Moretta A, Sun PD, Ugolini S, Vivier E. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13224-9. PMID:16141329 doi:10.1073/pnas.0503594102
4. ↑ Makadzange AT, Gillespie G, Dong T, Kiama P, Bwayo J, Kimani J, Plummer F, Easterbrook P, Rowland-Jones SL. Characterization of an HLA-C-restricted CTL response in chronic HIV infection. Eur J Immunol. 2010 Apr;40(4):1036-41. PMID:20104487 doi:10.1002/eji.200939634
5. ↑ Fadda L, Borhis G, Ahmed P, Cheent K, Pageon SV, Cazaly A, Stathopoulos S, Middleton D, Mulder A, Claas FH, Elliott T, Davis DM, Purbhoo MA, Khakoo SI. Peptide antagonism as a mechanism for NK cell activation. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10160-5. PMID:20439706 doi:10.1073/pnas.0913745107
6. ↑ Hiby SE, Apps R, Sharkey AM, Farrell LE, Gardner L, Mulder A, Claas FH, Walker JJ, Redman CW, Morgan L, Tower C, Regan L, Moore GE, Carrington M, Moffett A. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J Clin Invest. 2010 Nov;120(11):4102-10. PMID:20972337 doi:10.1172/JCI43998
7. ↑ Xiong S, Sharkey AM, Kennedy PR, Gardner L, Farrell LE, Chazara O, Bauer J, Hiby SE, Colucci F, Moffett A. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. J Clin Invest. 2013 Oct;123(10):4264-72. PMID:24091323 doi:10.1172/JCI68991
8. ↑ Rasmussen M, Harndahl M, Stryhn A, Boucherma R, Nielsen LL, Lemonnier FA, Nielsen M, Buus S. Uncovering the peptide-binding specificities of HLA-C: a general strategy to determine the specificity of any MHC class I molecule. J Immunol. 2014 Nov 15;193(10):4790-802. PMID:25311805 doi:10.4049/jimmunol.1401689
9. ↑ Kaur G, Gras S, Mobbs JI, Vivian JP, Cortes A, Barber T, Kuttikkatte SB, Jensen LT, Attfield KE, Dendrou CA, Carrington M, McVean G, Purcell AW, Rossjohn J, Fugger L. Structural and regulatory diversity shape HLA-C protein expression levels. Nat Commun. 2017 Jun 26;8:15924. doi: 10.1038/ncomms15924. PMID:28649982 doi:http://dx.doi.org/10.1038/ncomms15924
10. ↑ Hosie L, Pachnio A, Zuo J, Pearce H, Riddell S, Moss P. Cytomegalovirus-Specific T Cells Restricted by HLA-Cw*0702 Increase Markedly with Age and Dominate the CD8(+) T-Cell Repertoire in Older People. Front Immunol. 2017 Dec 11;8:1776. PMID:29312307 doi:10.3389/fimmu.2017.01776
11. ↑ Falk K, Rötzschke O, Grahovac B, Schendel D, Stevanović S, Gnau V, Jung G, Strominger JL, Rammensee HG. Allele-specific peptide ligand motifs of HLA-C molecules. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12005-9. PMID:8265661 doi:10.1073/pnas.90.24.12005
12. ↑ Kondo E, Akatsuka Y, Kuzushima K, Tsujimura K, Asakura S, Tajima K, Kagami Y, Kodera Y, Tanimoto M, Morishima Y, Takahashi T. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood. 2004 Jan 15;103(2):630-8. PMID:12947002 doi:10.1182/blood-2003-03-0824
13. ↑ Fadda L, Borhis G, Ahmed P, Cheent K, Pageon SV, Cazaly A, Stathopoulos S, Middleton D, Mulder A, Claas FH, Elliott T, Davis DM, Purbhoo MA, Khakoo SI. Peptide antagonism as a mechanism for NK cell activation. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10160-5. PMID:20439706 doi:10.1073/pnas.0913745107
14. ↑ Kondo E, Akatsuka Y, Kuzushima K, Tsujimura K, Asakura S, Tajima K, Kagami Y, Kodera Y, Tanimoto M, Morishima Y, Takahashi T. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood. 2004 Jan 15;103(2):630-8. PMID:12947002 doi:10.1182/blood-2003-03-0824
15. ↑ Makadzange AT, Gillespie G, Dong T, Kiama P, Bwayo J, Kimani J, Plummer F, Easterbrook P, Rowland-Jones SL. Characterization of an HLA-C-restricted CTL response in chronic HIV infection. Eur J Immunol. 2010 Apr;40(4):1036-41. PMID:20104487 doi:10.1002/eji.200939634
16. ↑ Addo MM, Altfeld M, Rosenberg ES, Eldridge RL, Philips MN, Habeeb K, Khatri A, Brander C, Robbins GK, Mazzara GP, Goulder PJ, Walker BD. The HIV-1 regulatory proteins Tat and Rev are frequently targeted by cytotoxic T lymphocytes derived from HIV-1-infected individuals. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1781-6. PMID:11172028 doi:10.1073/pnas.98.4.1781
17. ↑ Xiong S, Sharkey AM, Kennedy PR, Gardner L, Farrell LE, Chazara O, Bauer J, Hiby SE, Colucci F, Moffett A. Maternal uterine NK cell-activating receptor KIR2DS1 enhances placentation. J Clin Invest. 2013 Oct;123(10):4264-72. PMID:24091323 doi:10.1172/JCI68991
18. ↑ Hosie L, Pachnio A, Zuo J, Pearce H, Riddell S, Moss P. Cytomegalovirus-Specific T Cells Restricted by HLA-Cw*0702 Increase Markedly with Age and Dominate the CD8(+) T-Cell Repertoire in Older People. Front Immunol. 2017 Dec 11;8:1776. PMID:29312307 doi:10.3389/fimmu.2017.01776
19. ↑ Kondo E, Akatsuka Y, Kuzushima K, Tsujimura K, Asakura S, Tajima K, Kagami Y, Kodera Y, Tanimoto M, Morishima Y, Takahashi T. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood. 2004 Jan 15;103(2):630-8. PMID:12947002 doi:10.1182/blood-2003-03-0824
20. ↑ Choo JA, Liu J, Toh X, Grotenbreg GM, Ren EC. The immunodominant Influenza A virus M158-66 CTL epitope exhibits degenerate class I MHC restriction in humans. J Virol. 2014 Jul 2. pii: JVI.00855-14. PMID:24990997 doi:http://dx.doi.org/10.1128/JVI.00855-14
21. ↑ Kondo E, Akatsuka Y, Kuzushima K, Tsujimura K, Asakura S, Tajima K, Kagami Y, Kodera Y, Tanimoto M, Morishima Y, Takahashi T. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood. 2004 Jan 15;103(2):630-8. PMID:12947002 doi:10.1182/blood-2003-03-0824
22. ↑ Kondo E, Akatsuka Y, Kuzushima K, Tsujimura K, Asakura S, Tajima K, Kagami Y, Kodera Y, Tanimoto M, Morishima Y, Takahashi T. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood. 2004 Jan 15;103(2):630-8. PMID:12947002 doi:10.1182/blood-2003-03-0824
23. ↑ Moradi S, Stankovic S, O'Connor GM, Pymm P, MacLachlan BJ, Faoro C, Retière C, Sullivan LC, Saunders PM, Widjaja J, Cox-Livingstone S, Rossjohn J, Brooks AG, Vivian JP. Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C. Nat Commun. 2021 Apr 12;12(1):2173. PMID:33846289 doi:10.1038/s41467-021-22359-x