6v15

Structural highlights

Disease

DRB1_HUMAN Pediatric multiple sclerosis;Narcolepsy type 1;Narcolepsy type 2;Autoimmune pulmonary alveolar proteinosis;NON RARE IN EUROPE: Celiac disease;Systemic lupus erythematosus;Diffuse cutaneous systemic sclerosis;Giant cell arteritis;Follicular lymphoma;Limited cutaneous systemic sclerosis;NON RARE IN EUROPE: Rheumatoid arthritis;Sarcoidosis;Limited systemic sclerosis;Systemic-onset juvenile idiopathic arthritis;Bullous pemphigoid;NON RARE IN EUROPE: Multiple sclerosis;NON RARE IN EUROPE: Diabetes mellitus type 1. In populations of European descent, allele DRB1*01:03 is associated with increased susceptibility to Crohn disease and colonic ulcerative colitis. Decreased heterozygosity in individuals with colonic ulcerative colitis suggests that it acts as a recessive risk allele.^[1] Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:02, DRB1*11:01 and DRB1*12:01 are associated with sarcoidosis. Allele DRB1*04:02 is significantly associated with specific sarcodosis phenotypes such as eye, parotid and salivary gland involvement.^[2] Disease susceptibility is associated with variants affecting the gene represented in this entry. In populations of European descent, allele DRB1*15:01 has the strongest association with multiple sclerosis among all HLA class II alleles. Additional risk is associated with the strongly linked alleles DRB1*03:01 and DQB1*02:01 as well as with allele DRB1*13:03 (PubMed:21833088). It is postulated that bacterial or viral infection triggers the autoimmune MS. Microbial peptides having low affinity crossreactivity to MBP autoantigen, may stimulate autoreactive T cells via molecular mimicry and initiate the autoimmune inflammation (PubMed:19303388).^{[3] [4]} Allele DRB1*15:01 is associated with increased susceptibility to Goodpasture syndrome. Can present a self-peptide derived from COL4A3 (GWISLWKGFSF) on TCR (TRAV19 biased) in pathogenic CD4-positive T-helper 1 and T-helper 17 cells, triggering autoimmune inflammation.^[5] Disease susceptibility is associated with variants affecting the gene represented in this entry. Alleles DRB1*04:01; DRB1*04:04; DRB1*04:05; DRB1*04:08; DRB1*10:01; DRB1*01:01 and DRB1*01:02 are associated with increased susceptibility to rheumatoid arthritis, where affected individuals have antibodies to cyclic citrullinated peptide (anti-CCP-positive rheumatoid arthritis). Variations at position 40 in the peptide-binding cleft of these alleles explain most of the association to rheumatoid arthritis risk.^[6]

Function

DRB1_HUMAN A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule. In complex with the alpha chain HLA-DRA, displays antigenic peptides on professional antigen presenting cells (APCs) for recognition by alpha-beta T cell receptor (TCR) on HLA-DRB1-restricted CD4-positive T cells. This guides antigen-specific T-helper effector functions, both antibody-mediated immune response and macrophage activation, to ultimately eliminate the infectious agents and transformed cells (PubMed:29884618, PubMed:22327072, PubMed:27591323, PubMed:8642306, PubMed:15265931, PubMed:31495665, PubMed:16148104). Typically presents extracellular peptide antigens of 10 to 30 amino acids that arise from proteolysis of endocytosed antigens in lysosomes (PubMed:8145819). In the tumor microenvironment, presents antigenic peptides that are primarily generated in tumor-resident APCs likely via phagocytosis of apoptotic tumor cells or macropinocytosis of secreted tumor proteins (PubMed:31495665). Presents peptides derived from intracellular proteins that are trapped in autolysosomes after macroautophagy, a mechanism especially relevant for T cell selection in the thymus and central immune tolerance (PubMed:17182262, PubMed:23783831). The selection of the immunodominant epitopes follows two processing modes: 'bind first, cut/trim later' for pathogen-derived antigenic peptides and 'cut first, bind later' for autoantigens/self-peptides (PubMed:25413013). The anchor residue at position 1 of the peptide N-terminus, usually a large hydrophobic residue, is essential for high affinity interaction with MHCII molecules (PubMed:8145819).^{[7] [8] [9] [10] [11] [12] [13] [14] [15] [16]} Allele DRB1*01:01: Displays an immunodominant epitope derived from Bacillus anthracis pagA/protective antigen, PA (KLPLYISNPNYKVNVYAVT), to both naive and PA-specific memory CD4-positive T cells (PubMed:22327072). Presents immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (PHQFINLRSNNSATLIVPYV), contributing to viral clearance (PubMed:27591323). Displays commonly recognized peptides derived from IAV external protein HA (PKYVKQNTLKLAT and SNGNFIAPEYAYKIVK) and from internal proteins M, NP and PB1, with M-derived epitope (GLIYNRMGAVTTEV) being the most immunogenic (PubMed:8145819, PubMed:9075930, PubMed:25413013, PubMed:32668259). Presents a self-peptide derived from COL4A3 (GWISLWKGFSF) to TCR (TRAV14 biased) on CD4-positive, FOXP3-positive regulatory T cells and mediates immune tolerance to self (PubMed:28467828). May present peptides derived from oncofetal trophoblast glycoprotein TPBG 5T4, known to be recognized by both T-helper 1 and regulatory T cells (PubMed:31619516). Displays with low affinity a self-peptide derived from MBP (VHFFKNIVTPRTP) (PubMed:9075930).^{[17] [18] [19] [20] [21] [22] [23] [24] [25]} Allele DRB1*03:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Displays self-peptides derived from retinal SAG (NRERRGIALDGKIKHE) and thyroid TG (LSSVVVDPSIRHFDV) (PubMed:25413013). Presents viral epitopes derived from HHV-6B gH/U48 and U85 antigens to polyfunctional CD4-positive T cells with cytotoxic activity implicated in control of HHV-6B infection (PubMed:31020640). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and long-term protection (PubMed:19830726).^{[26] [27] [28] [29]} Allele DRB1*04:01: Presents an immunodominant bacterial epitope derived from M. tuberculosis esxB/culture filtrate antigen CFP-10 (EISTNIRQAGVQYSR), eliciting CD4-positive T cell effector functions such as IFNG production and cytotoxic activity (PubMed:15265931). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (NEKQPSDDNWLNFDGTLLGN), contributing to viral clearance (PubMed:27591323). Presents tumor epitopes derived from melanoma-associated TYR antigen (QNILLSNAPLGPQFP and DYSYLQDSDPDSFQD), triggering CD4-positive T cell effector functions such as GMCSF production (PubMed:8642306). Displays preferentially citrullinated self-peptides derived from VIM (GVYATR/citSSAVR and SAVRAR/citSSVPGVR) and ACAN (VVLLVATEGR/ CitVRVNSAYQDK) (PubMed:24190431). Displays self-peptides derived from COL2A1 (PubMed:9354468).^{[30] [31] [32] [33] [34]} Allele DRB1*04:02: Displays native or citrullinated self-peptides derived from VIM.^[35] Allele DRB1*04:04: May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (HIVMQYMYVPPGAPIPTTRN) and VP2 (RGDSTITSQDVANAVVGYGV), contributing to viral clearance (PubMed:27591323). Displays preferentially citrullinated self-peptides derived from VIM (SAVRAR/citSSVPGVR) (PubMed:24190431).^{[36] [37]} Allele DRB1*04:05: May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.^[38] Allele DRB1*05:01: Presents an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load.^[39] Allele DRB1*07:01: Upon EBV infection, presents latent antigen EBNA2 peptide (PRSPTVFYNIPPMPLPPSQL) to CD4-positive T cells, driving oligoclonal expansion and selection of a dominant virus-specific memory T cell subset with cytotoxic potential to directly eliminate virus-infected B cells (PubMed:31308093). May present to T-helper 1 cells several HRV-16 epitopes derived from capsid proteins VP1 (PRFSLPFLSIASAYYMFYDG) and VP2 (VPYVNAVPMDSMVRHNNWSL), contributing to viral clearance (PubMed:27591323). In the context of tumor immunesurveillance, may present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (MTEYKLVVVGAVGVGKSALTIQLI), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:22929521). In metastatic epithelial tumors, presents to intratumoral CD4-positive T cells a KRAS neoantigen (MTEYKLVVVGAVGVGKSALTIQLI) carrying G12V hotspot driver mutation and may mediate tumor regression (PubMed:30282837).^{[40] [41] [42] [43]} Allele DRB1*11:01: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SDRIIQITRGDSTITSQDVA), contributing to viral clearance (PubMed:27591323). Presents several immunogenic epitopes derived from C. tetani neurotoxin tetX, playing a role in immune recognition and longterm protection (PubMed:19830726). In the context of tumor immunesurveillance, may present tumor-derived neoantigens to CD4-positive T cells and trigger anti-tumor helper functions (PubMed:31495665).^{[44] [45] [46] [47]} Allele DRB1*13:01: Presents viral epitopes derived from HHV-6B antigens to polyfunctional CD4-positive T cells implicated in control of HHV-6B infection.^[48] Allele DRB1*15:01: May present to T-helper 1 cells an HRV-16 epitope derived from capsid protein VP2 (SNNSATLIVPYVNAVPMDSM), contributing to viral clearance (PubMed:27591323). Displays a self-peptide derived from MBP (ENPVVHFFKNIVTPR) (PubMed:9782128, PubMed:25413013). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies.^{[49] [50] [51]} Allele DRB1*15:02: Displays an immunodominant HIV-1 gag peptide (FRDYVDRFYKTLRAEQASQE) on infected dendritic cells for recognition by TRAV24-TRBV2 TCR on CD4-positive T cells and controls viral load (PubMed:29884618). May present to T-helper 1 cells an immunogenic epitope derived from tumor-associated antigen WT1 (KRYFKLSHLQMHSRKH), likely providing for effective antitumor immunity in a wide range of solid and hematological malignancies (PubMed:19120973).^{[52] [53]} (Microbial infection) Acts as a receptor for Epstein-Barr virus on lymphocytes.^{[54] [55]}

See Also

• MHC 3D structures
• MHC II 3D structures

References

1. ↑ Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S, Daly MJ, Van Steen K, Duerr RH, Barrett JC, McGovern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Nat Genet. 2015 Feb;47(2):172-9. PMID:25559196 doi:10.1038/ng.3176
2. ↑ Rossman MD, Thompson B, Frederick M, Maliarik M, Iannuzzi MC, Rybicki BA, Pandey JP, Newman LS, Magira E, Beznik-Cizman B, Monos D. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet. 2003 Oct;73(4):720-35. Epub 2003 Aug 20. PMID:14508706 doi:10.1086/378097
3. ↑ Harkiolaki M, Holmes SL, Svendsen P, Gregersen JW, Jensen LT, McMahon R, Friese MA, van Boxel G, Etzensperger R, Tzartos JS, Kranc K, Sainsbury S, Harlos K, Mellins ED, Palace J, Esiri MM, van der Merwe PA, Jones EY, Fugger L. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity. 2009 Mar 20;30(3):348-57. PMID:19303388 doi:10.1016/j.immuni.2009.01.009
4. ↑ Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D'alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D'hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppä V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Rückert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sørensen PS, Søndergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvänen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011 Aug 10;476(7359):214-9. PMID:21833088 doi:10.1038/nature10251
5. ↑ Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA, Gan PY, Alikhan MA, Dudek NL, Handel A, Hudson BG, Fugger L, Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW, Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J, Kitching AR. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature. 2017 May 11;545(7653):243-247. doi: 10.1038/nature22329. Epub 2017 May 3. PMID:28467828 doi:http://dx.doi.org/10.1038/nature22329
6. ↑ Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, Alfredsson L, Padyukov L, Klareskog L, Worthington J, Siminovitch KA, Bae SC, Plenge RM, Gregersen PK, de Bakker PI. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012 Jan 29;44(3):291-6. doi: 10.1038/ng.1076. PMID:22286218 doi:http://dx.doi.org/10.1038/ng.1076
7. ↑ Shams H, Klucar P, Weis SE, Lalvani A, Moonan PK, Safi H, Wizel B, Ewer K, Nepom GT, Lewinsohn DM, Andersen P, Barnes PF. Characterization of a Mycobacterium tuberculosis peptide that is recognized by human CD4+ and CD8+ T cells in the context of multiple HLA alleles. J Immunol. 2004 Aug 1;173(3):1966-77. PMID:15265931 doi:10.4049/jimmunol.173.3.1966
8. ↑ Schmid D, Pypaert M, Münz C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity. 2007 Jan;26(1):79-92. PMID:17182262 doi:10.1016/j.immuni.2006.10.018
9. ↑ Kwok WW, Tan V, Gillette L, Littell CT, Soltis MA, LaFond RB, Yang J, James EA, DeLong JH. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. J Immunol. 2012 Mar 15;188(6):2537-44. PMID:22327072 doi:10.4049/jimmunol.1102190
10. ↑ Adamopoulou E, Tenzer S, Hillen N, Klug P, Rota IA, Tietz S, Gebhardt M, Stevanovic S, Schild H, Tolosa E, Melms A, Stoeckle C. Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nat Commun. 2013;4:2039. PMID:23783831 doi:10.1038/ncomms3039
11. ↑ Kim A, Hartman IZ, Poore B, Boronina T, Cole RN, Song N, Ciudad MT, Caspi RR, Jaraquemada D, Sadegh-Nasseri S. Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun. 2014 Nov 21;5:5369. PMID:25413013 doi:10.1038/ncomms6369
12. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
13. ↑ Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:http://dx.doi.org/10.1126/sciimmunol.aat0687
14. ↑ Abelin JG, Harjanto D, Malloy M, Suri P, Colson T, Goulding SP, Creech AL, Serrano LR, Nasir G, Nasrullah Y, McGann CD, Velez D, Ting YS, Poran A, Rothenberg DA, Chhangawala S, Rubinsteyn A, Hammerbacher J, Gaynor RB, Fritsch EF, Greshock J, Oslund RC, Barthelme D, Addona TA, Arieta CM, Rooney MS. Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction. Immunity. 2019 Oct 15;51(4):766-779.e17. PMID:31495665 doi:10.1016/j.immuni.2019.08.012
15. ↑ Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994 Mar 17;368(6468):215-21. PMID:8145819 doi:http://dx.doi.org/10.1038/368215a0
16. ↑ Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, Robbins PF. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med. 1996 May 1;183(5):1965-71. PMID:8642306 doi:10.1084/jem.183.5.1965
17. ↑ Kwok WW, Tan V, Gillette L, Littell CT, Soltis MA, LaFond RB, Yang J, James EA, DeLong JH. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. J Immunol. 2012 Mar 15;188(6):2537-44. PMID:22327072 doi:10.4049/jimmunol.1102190
18. ↑ Kim A, Hartman IZ, Poore B, Boronina T, Cole RN, Song N, Ciudad MT, Caspi RR, Jaraquemada D, Sadegh-Nasseri S. Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun. 2014 Nov 21;5:5369. PMID:25413013 doi:10.1038/ncomms6369
19. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
20. ↑ Ooi JD, Petersen J, Tan YH, Huynh M, Willett ZJ, Ramarathinam SH, Eggenhuizen PJ, Loh KL, Watson KA, Gan PY, Alikhan MA, Dudek NL, Handel A, Hudson BG, Fugger L, Power DA, Holt SG, Coates PT, Gregersen JW, Purcell AW, Holdsworth SR, La Gruta NL, Reid HH, Rossjohn J, Kitching AR. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature. 2017 May 11;545(7653):243-247. doi: 10.1038/nature22329. Epub 2017 May 3. PMID:28467828 doi:http://dx.doi.org/10.1038/nature22329
21. ↑ Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:http://dx.doi.org/10.1126/sciimmunol.aat0687
22. ↑ MacLachlan BJ, Dolton G, Papakyriakou A, Greenshields-Watson A, Mason GH, Schauenburg A, Besneux M, Szomolay B, Elliott T, Sewell AK, Gallimore A, Rizkallah P, Cole DK, Godkin A. Human leukocyte antigen (HLA) class II peptide flanking residues tune the immunogenicity of a human tumor-derived epitope. J Biol Chem. 2019 Oct 16. pii: RA119.009437. doi: 10.1074/jbc.RA119.009437. PMID:31619516 doi:http://dx.doi.org/10.1074/jbc.RA119.009437
23. ↑ Greenshields-Watson A, Attaf M, MacLachlan BJ, Whalley T, Rius C, Wall A, Lloyd A, Hughes H, Strange KE, Mason GH, Schauenburg AJ, Hulin-Curtis SL, Geary J, Chen Y, Lauder SN, Smart K, Vijaykrishna D, Grau ML, Shugay M, Andrews R, Dolton G, Rizkallah PJ, Gallimore AM, Sewell AK, Godkin AJ, Cole DK. CD4(+) T Cells Recognize Conserved Influenza A Epitopes through Shared Patterns of V-Gene Usage and Complementary Biochemical Features. Cell Rep. 2020 Jul 14;32(2):107885. PMID:32668259 doi:10.1016/j.celrep.2020.107885
24. ↑ Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature. 1994 Mar 17;368(6468):215-21. PMID:8145819 doi:http://dx.doi.org/10.1038/368215a0
25. ↑ Kropshofer H, Arndt SO, Moldenhauer G, Hämmerling GJ, Vogt AB. HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH. Immunity. 1997 Mar;6(3):293-302. PMID:9075930 doi:10.1016/s1074-7613(00)80332-5
26. ↑ Faner R, James E, Huston L, Pujol-Borrel R, Kwok WW, Juan M. Reassessing the role of HLA-DRB3 T-cell responses: evidence for significant expression and complementary antigen presentation. Eur J Immunol. 2010 Jan;40(1):91-102. PMID:19830726 doi:10.1002/eji.200939225
27. ↑ Kim A, Hartman IZ, Poore B, Boronina T, Cole RN, Song N, Ciudad MT, Caspi RR, Jaraquemada D, Sadegh-Nasseri S. Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources. Nat Commun. 2014 Nov 21;5:5369. PMID:25413013 doi:10.1038/ncomms6369
28. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
29. ↑ Becerra-Artiles A, Cruz J, Leszyk JD, Sidney J, Sette A, Shaffer SA, Stern LJ. Naturally processed HLA-DR3-restricted HHV-6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses. Eur J Immunol. 2019 Aug;49(8):1167-1185. PMID:31020640 doi:10.1002/eji.201948126
30. ↑ Shams H, Klucar P, Weis SE, Lalvani A, Moonan PK, Safi H, Wizel B, Ewer K, Nepom GT, Lewinsohn DM, Andersen P, Barnes PF. Characterization of a Mycobacterium tuberculosis peptide that is recognized by human CD4+ and CD8+ T cells in the context of multiple HLA alleles. J Immunol. 2004 Aug 1;173(3):1966-77. PMID:15265931 doi:10.4049/jimmunol.173.3.1966
31. ↑ Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, McCluskey J, Toes RE, La Gruta NL, Purcell AW, Reid HH, Thomas R, Rossjohn J. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013 Nov 18;210(12):2569-82. doi: 10.1084/jem.20131241. Epub 2013 Nov , 4. PMID:24190431 doi:http://dx.doi.org/10.1084/jem.20131241
32. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
33. ↑ Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, Robbins PF. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med. 1996 May 1;183(5):1965-71. PMID:8642306 doi:10.1084/jem.183.5.1965
34. ↑ Dessen A, Lawrence CM, Cupo S, Zaller DM, Wiley DC. X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity. 1997 Oct;7(4):473-81. PMID:9354468
35. ↑ Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, McCluskey J, Toes RE, La Gruta NL, Purcell AW, Reid HH, Thomas R, Rossjohn J. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013 Nov 18;210(12):2569-82. doi: 10.1084/jem.20131241. Epub 2013 Nov , 4. PMID:24190431 doi:http://dx.doi.org/10.1084/jem.20131241
36. ↑ Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, Wijeyewickrema LC, Eckle SB, van Heemst J, Pike RN, McCluskey J, Toes RE, La Gruta NL, Purcell AW, Reid HH, Thomas R, Rossjohn J. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013 Nov 18;210(12):2569-82. doi: 10.1084/jem.20131241. Epub 2013 Nov , 4. PMID:24190431 doi:http://dx.doi.org/10.1084/jem.20131241
37. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
38. ↑ Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Nakajima H, Elisseeva OA, Harada Y, Li Z, Tatsumi N, Kamino E, Shirakata T, Nishida S, Taniguchi Y, Kawase I, Oji Y, Sugiyama H. A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cells. Microbiol Immunol. 2008 Dec;52(12):591-600. PMID:19120973 doi:10.1111/j.1348-0421.2008.00080.x
39. ↑ Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:http://dx.doi.org/10.1126/sciimmunol.aat0687
40. ↑ Anguille S, Fujiki F, Smits EL, Oji Y, Lion E, Oka Y, Berneman ZN, Sugiyama H. Identification of a Wilms' tumor 1-derived immunogenic CD4(+) T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes. Leukemia. 2013 Mar;27(3):748-50. PMID:22929521 doi:10.1038/leu.2012.248
41. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
42. ↑ Yossef R, Tran E, Deniger DC, Gros A, Pasetto A, Parkhurst MR, Gartner JJ, Prickett TD, Cafri G, Robbins PF, Rosenberg SA. Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy. JCI Insight. 2018 Oct 4;3(19):e122467. PMID:30282837 doi:10.1172/jci.insight.122467
43. ↑ Meckiff BJ, Ladell K, McLaren JE, Ryan GB, Leese AM, James EA, Price DA, Long HM. Primary EBV Infection Induces an Acute Wave of Activated Antigen-Specific Cytotoxic CD4(+) T Cells. J Immunol. 2019 Sep 1;203(5):1276-1287. PMID:31308093 doi:10.4049/jimmunol.1900377
44. ↑ Faner R, James E, Huston L, Pujol-Borrel R, Kwok WW, Juan M. Reassessing the role of HLA-DRB3 T-cell responses: evidence for significant expression and complementary antigen presentation. Eur J Immunol. 2010 Jan;40(1):91-102. PMID:19830726 doi:10.1002/eji.200939225
45. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
46. ↑ Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:http://dx.doi.org/10.1126/sciimmunol.aat0687
47. ↑ Abelin JG, Harjanto D, Malloy M, Suri P, Colson T, Goulding SP, Creech AL, Serrano LR, Nasir G, Nasrullah Y, McGann CD, Velez D, Ting YS, Poran A, Rothenberg DA, Chhangawala S, Rubinsteyn A, Hammerbacher J, Gaynor RB, Fritsch EF, Greshock J, Oslund RC, Barthelme D, Addona TA, Arieta CM, Rooney MS. Defining HLA-II Ligand Processing and Binding Rules with Mass Spectrometry Enhances Cancer Epitope Prediction. Immunity. 2019 Oct 15;51(4):766-779.e17. PMID:31495665 doi:10.1016/j.immuni.2019.08.012
48. ↑ Becerra-Artiles A, Cruz J, Leszyk JD, Sidney J, Sette A, Shaffer SA, Stern LJ. Naturally processed HLA-DR3-restricted HHV-6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses. Eur J Immunol. 2019 Aug;49(8):1167-1185. PMID:31020640 doi:10.1002/eji.201948126
49. ↑ Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Nakajima H, Elisseeva OA, Harada Y, Li Z, Tatsumi N, Kamino E, Shirakata T, Nishida S, Taniguchi Y, Kawase I, Oji Y, Sugiyama H. A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cells. Microbiol Immunol. 2008 Dec;52(12):591-600. PMID:19120973 doi:10.1111/j.1348-0421.2008.00080.x
50. ↑ Muehling LM, Mai DT, Kwok WW, Heymann PW, Pomés A, Woodfolk JA. Circulating Memory CD4+ T Cells Target Conserved Epitopes of Rhinovirus Capsid Proteins and Respond Rapidly to Experimental Infection in Humans. J Immunol. 2016 Oct 15;197(8):3214-3224. PMID:27591323 doi:10.4049/jimmunol.1600663
51. ↑ Smith KJ, Pyrdol J, Gauthier L, Wiley DC, Wucherpfennig KW. Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. J Exp Med. 1998 Oct 19;188(8):1511-20. PMID:9782128
52. ↑ Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Nakajima H, Elisseeva OA, Harada Y, Li Z, Tatsumi N, Kamino E, Shirakata T, Nishida S, Taniguchi Y, Kawase I, Oji Y, Sugiyama H. A WT1 protein-derived, naturally processed 16-mer peptide, WT1(332), is a promiscuous helper peptide for induction of WT1-specific Th1-type CD4(+) T cells. Microbiol Immunol. 2008 Dec;52(12):591-600. PMID:19120973 doi:10.1111/j.1348-0421.2008.00080.x
53. ↑ Galperin M, Farenc C, Mukhopadhyay M, Jayasinghe D, Decroos A, Benati D, Tan LL, Ciacchi L, Reid HH, Rossjohn J, Chakrabarti LA, Gras S. CD4(+) T cell-mediated HLA class II cross-restriction in HIV controllers. Sci Immunol. 2018 Jun 8;3(24). pii: 3/24/eaat0687. doi:, 10.1126/sciimmunol.aat0687. PMID:29884618 doi:http://dx.doi.org/10.1126/sciimmunol.aat0687
54. ↑ Mullen MM, Haan KM, Longnecker R, Jardetzky TS. Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II receptor HLA-DR1. Mol Cell. 2002 Feb;9(2):375-85. PMID:11864610
55. ↑ Li Q, Spriggs MK, Kovats S, Turk SM, Comeau MR, Nepom B, Hutt-Fletcher LM. Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J Virol. 1997 Jun;71(6):4657-62. PMID:9151859 doi:10.1128/JVI.71.6.4657-4662.1997
56. ↑ Lim JJ, Jones CM, Loh TJ, Ting YT, Zareie P, Loh KL, Felix NJ, Suri A, McKinnon M, Stevenaert F, Sharma RK, Klareskog L, Malmström V, Baker DG, Purcell AW, Reid HH, La Gruta NL, Rossjohn J. The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR. Sci Immunol. 2021 Apr 16;6(58):eabe0896. PMID:33863750 doi:10.1126/sciimmunol.abe0896