Abstract
B*38:01 and B*39:06 are present with phenotypic frequencies <2 % in the general population, but are of interest as B*39:06 is the B allele most associated with type 1 diabetes susceptibility and 38:01 is most protective. A previous study derived putative main anchor motifs for both alleles based on peptide elution data. The present study has utilized panels of single amino acid substitution peptide libraries to derive detailed quantitative motifs accounting for both primary and secondary influences on peptide binding. From these analyses, both alleles were confirmed to utilize the canonical position 2/C-terminus main anchor spacing. B*38:01 preferentially bound peptides with the positively charged or polar residues H, R, and Q in position 2 and the large hydrophobic residues I, F, L, W, and M at the C-terminus. B*39:06 had a similar preference for R in position 2, but also well-tolerated M, Q, and K. A more dramatic contrast between the two alleles was noted at the C-terminus, where the specificity of B*39:06 was clearly for small residues, with A as most preferred, followed by G, V, S, T, and I. Detailed position-by-position and residue-by-residue coefficient values were generated from the panels to provide detailed quantitative B*38:01 and B*39:06 motifs. It is hoped that these detailed motifs will facilitate the identification of T cell epitopes recognized in the context of two class I alleles associated with dramatically different dispositions towards type 1 diabetes, offering potential avenues for the investigation of the role of CD8 T cells in this disease.
This is a preview of subscription content, log in via an institution to check access.
References
Bettini M, Vignali DA (2011) T cell-driven initiation and propagation of autoimmune diabetes. Curr Opin Immunol 23:754–760
Brims DR, Qian J, Jarchum I, Mikesh L, Palmieri E, Ramagopal UA, Malashkevich VN, Chaparro RJ, Lund T, Hattori M, Shabanowitz J, Hunt DF, Nathenson SG, Almo SC, Dilorenzo TP (2010) Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect. Int Immunol 22:191–203
Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, Roep BO, von Herrath MG (2012) Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 209:51–60
Doolan DL, Southwood S, Freilich DA, Sidney J, Graber NL, Shatney L, Bebris L, Florens L, Dobano C, Witney AA, Appella E, Hoffman SL, Yates JR 3rd, Carucci DJ, Sette A (2003) Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data. Proc Natl Acad Sci U S A 100:9952–9957
Eichmann M, de Ru A, van Veelen PA, Peakman M, Kronenberg-Versteeg D (2014) Identification and characterisation of peptide binding motifs of six autoimmune disease-associated human leukocyte antigen-class I molecules including HLA-B*39:06. Tissue Antigens 84:378–388
Falk K, Rotzschke O, Takiguchi M, Gnau V, Stevanovic S, Jung G, Rammensee HG (1995) Peptide motifs of HLA-B38 and B39 molecules. Immunogenetics 41:162–164
Howson JM, Walker NM, Clayton D, Todd JA (2009) Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A. Diabetes Obes Metab 11(Suppl 1):31–45
Khankhanian P, Matsushita T, Madireddy L, Lizee A, Din L, More JM, Gourraud PA, Hauser SL, Baranzini SE, Oksenberg JR (2015) Genetic contribution to multiple sclerosis risk among Ashkenazi Jews. BMC Med Genet 16:55
Knight RR, Kronenberg D, Zhao M, Huang GC, Eichmann M, Bulek A, Wooldridge L, Cole DK, Sewell AK, Peakman M, Skowera A (2013) Human beta-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity. Diabetes 62:205–213
Matsumura M, Fremont DH, Peterson PA, Wilson IA (1992) Emerging principles for the recognition of peptide antigens by MHC class I molecules. Science 257:927–934
Mortazavi H, Amirzargar AA, Esmaili N, Toofan H, Ehsani AH, Hosseini SH, Rezaei N (2013) Association of human leukocyte antigen class I antigens in Iranian patients with pemphigus vulgaris. J Dermatol 40:244–248
Moutaftsi M, Peters B, Pasquetto V, Tscharke DC, Sidney J, Bui HH, Grey H, Sette A (2006) A consensus epitope prediction approach identifies the breadth of murine T(CD8+)-cell responses to vaccinia virus. Nat Biotechnol 24:817–819
Mukherjee G, Chaparro RJ, Schloss J, Smith C, Bando CD, DiLorenzo TP (2015) Glucagon-reactive islet-infiltrating CD8 T cells in NOD mice. Immunology 144:631–640
Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P, Hardy M, King E, Masters J, Hulme J, Maier LM, Smyth D, Bailey R, Cooper JD, Ribas G, Campbell RD, Clayton DG, Todd JA (2007) Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450:887–892
Noble JA, Valdes AM, Varney MD, Carlson JA, Moonsamy P, Fear AL, Lane JA, Lavant E, Rappner R, Louey A, Concannon P, Mychaleckyj JC, Erlich HA (2010) HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes 59:2972–2979
Peters B, Bui H-H, Frankild S, Nielsen M, Lundegaard C, Kostem E, Basch D, Lamberth K, Harndahl M, Fleri W, Wilson SS, Sidney J, Lund O, Buus S, Sette A (2006) A community resource benchmarking predictions of peptide binding to MHC-I molecules. PLoS Comput Biol 2, e65
Reed JS, Sidney J, Piaskowski SM, Glidden CE, Leon EJ, Burwitz BJ, Kolar HL, Eernisse CM, Furlott JR, Maness NJ, Walsh AD, Rudersdorf RA, Bardet W, McMurtrey CP, O’Connor DH, Hildebrand WH, Sette A, Watkins DI, Wilson NA (2011) The role of MHC class I allele Mamu-A*07 during SIV(mac)239 infection. Immunogenetics 63:789–807
Rodriguez-Reyna TS, Zuniga-Ramos J, Salgado N, Hernandez-Martinez B, Vargas-Alarcon G, Reyes-Lopez PA, Granados J (1998) Intron 2 and exon 3 sequences may be involved in the susceptibility to develop Takayasu arteritis. Int J Cardiol 66(Suppl 1):S135–S138, discussion S139
Rosmalen JG, van Ewijk W, Leenen PJ (2002) T-cell education in autoimmune diabetes: teachers and students. Trends Immunol 23:40–46
Salazar M, Varela A, Ramirez LA, Uribe O, Vasquez G, Egea E, Yunis EJ, Iglesias-Gamarra A (2000) Association of HLA-DRB1*1602 and DRB1*1001 with Takayasu arteritis in Colombian mestizos as markers of Amerindian ancestry. Int J Cardiol 75(Suppl 1):S113–S116
Saper MA, Bjorkman PJ, Wiley DC (1991) Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution. J Mol Biol 219:277–319
Serreze DV, Leiter EH, Christianson GJ, Greiner D, Roopenian DC (1994) Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Diabetes 43:505–509
Sette A (2000) Tools of the trade in vaccine design. Science 290:2074–2075
Sette A, Fikes J (2003) Epitope-based vaccines: an update on epitope identification, vaccine design and delivery. Curr Opin Immunol 15:461–470
Sette A, Livingston B, McKinney D, Appella E, Fikes J, Sidney J, Newman M, Chesnut R (2001) The development of multi-epitope vaccines: epitope identification, vaccine design and clinical evaluation. Biologicals 29:271–276
Sette A, Peters B (2007) Immune epitope mapping in the post-genomic era: lessons for vaccine development. Curr Opin Immunol 19:106–110
Sette A, Rappuoli R (2010) Reverse vaccinology: developing vaccines in the Era of genomics. Immunity 33:530–541
Sette A, Sidney J (1999) Nine major HLA class I supertypes account for the vast preponderance of HLA-A and -B polymorphism. Immunogenetics 50:201–212
Sidney J, Assarsson E, Moore C, Ngo S, Pinilla C, Sette A, Peters B (2008a) Quantitative peptide binding motifs for 19 human and mouse MHC class I molecules derived using positional scanning combinatorial peptide libraries. Immunome Res 4:2
Sidney J, Peters B, Frahm N, Brander C, Sette A (2008b) HLA class I supertypes: a revised and updated classification. BMC Immunol 9:1
Sidney J, Southwood S, Moore C, Oseroff C, Pinilla C, Grey HM, Sette A (2013) Measurement of MHC/peptide interactions by gel filtration or monoclonal antibody capture. Current protocols in immunology / edited by John E. Coligan … [et al.] Chapter 18:Unit 18 3
Srinivasan M, Frauwirth KA (2009) Peripheral tolerance in CD8+ T cells. Cytokine 46:147–159
Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711
Trolle T, Metushi IG, Greenbaum JA, Kim Y, Sidney J, Lund O, Sette A, Peters B, Nielsen M (2015) Automated benchmarking of peptide-MHC class I binding predictions., Bioinformatics
Vargas-Alarcon G, Hernandez-Pacheco G, Soto ME, Murguia LE, Perez-Hernandez N, Granados J, Reyes PA (2005) Comparative study of the residues 63 and 67 on the HLA-B molecule in patients with Takayasu’s Arteritis. Immunol Lett 96:225–229
Walter U, Santamaria P (2005) CD8+ T cells in autoimmunity. Curr Opin Immunol 17:624–631
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR, Vignali DA (2009) The development and function of regulatory T cells. Cell Mol Life Sci 66:2603–2622
Acknowledgments
The experiments described herein comply with the current laws of the United States of America. This work was supported by the National Institutes of Health (National Institutes for Allergy and Infectious Diseases) contracts and grants HHSN272201400045C (A.S.), R01 DK094327, R01 DK064315, and R03 AI119225 to T.P.D.; T32 GM007288 and F30 DK103368, which supported J.S.; and P60 DK020541, which supports the Diabetes Research Center of the Albert Einstein College of Medicine. T.P.D. is the Diane Belfer, Cypres and Endelson Families Faculty Scholar in Diabetes Research.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
Supplemental Table 1. B*38:01 SAAS IC50 nM. Supplemental Table 2. B*39:06 SAAS IC50 nM. Supplemental Table 3. Pilot validation peptides. (XLSX 45 kb)
Rights and permissions
About this article
Cite this article
Sidney, J., Schloss, J., Moore, C. et al. Characterization of the peptide binding specificity of the HLA class I alleles B*38:01 and B*39:06. Immunogenetics 68, 231–236 (2016). https://doi.org/10.1007/s00251-015-0898-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-015-0898-2