Sampling From the Proteome to the Human Leukocyte Antigen-DR (HLA-DR) Ligandome Proceeds Via High Specificity

被引:50
|
作者
Mommen, Geert P. M. [1 ,2 ,3 ]
Marino, Fabio [2 ,3 ,4 ]
Meiring, Hugo D. [1 ]
Poelen, Martien C. M. [5 ]
van Gaans-van den Brink, Jacqueline A. M. [5 ]
Mohammed, Shabaz [2 ,3 ,4 ,6 ,7 ]
Heck, Albert J. R. [2 ,3 ,4 ]
van Els, Cecile A. C. M. [5 ]
机构
[1] Inst Translat Vaccinol, POB 450, NL-3720 AL Bilthoven, Netherlands
[2] Univ Utrecht, Fac Sci, Biomol Mass Spectrometry & Protem, Bijvoet Ctr Biomol Res, Padualaan 8, NL-3584 CH Utrecht, Netherlands
[3] Univ Utrecht, Fac Sci, Inst Pharmaceut Sci, Padualaan 8, NL-3584 CH Utrecht, Netherlands
[4] Netherlands Prote Ctr, Padualaan 8, NL-3584 CH Utrecht, Netherlands
[5] Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, POB 1, NL-3720 AL Bilthoven, Netherlands
[6] Univ Oxford, Dept Chem, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA, England
[7] Univ Oxford, Dept Biochem, S Parks Rd, Oxford OX1 3QU, England
关键词
MHC CLASS-I; DISSOCIATION MASS-SPECTROMETRY; T-CELL RESPONSES; DENDRITIC CELLS; ELECTRON-TRANSFER; PEPTIDE IDENTIFICATION; CROSS-PRESENTATION; BOUND PEPTIDES; HUMAN THYMUS; AUTOPHAGY;
D O I
10.1074/mcp.M115.055780
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Comprehensive analysis of the complex nature of the Human Leukocyte Antigen (HLA) class II ligandome is of utmost importance to understand the basis for CD4(+) T cell mediated immunity and tolerance. Here, we implemented important improvements in the analysis of the repertoire of HLA-DR-presented peptides, using hybrid mass spectrometry-based peptide fragmentation techniques on a ligandome sample isolated from matured human monocyte-derived dendritic cells (DC). The reported data set constitutes nearly 14 thousand unique high-confident peptides, i.e. the largest single inventory of human DC derived HLA-DR ligands to date. From a technical viewpoint the most prominent finding is that no single peptide fragmentation technique could elucidate the majority of HLA-DR ligands, because of the wide range of physical chemical properties displayed by the HLA-DR ligandome. Our in-depth profiling allowed us to reveal a strikingly poor correlation between the source proteins identified in the HLA class II ligandome and the DC cellular proteome. Important selective sieving from the sampled proteome to the ligandome was evidenced by specificity in the sequences of the core regions both at their N- and C- termini, hence not only reflecting binding motifs but also dominant protease activity associated to the endolysosomal compartments. Moreover, we demonstrate that the HLA-DR ligandome reflects a surface representation of cell-compartments specific for biological events linked to the maturation of monocytes into antigen presenting cells. Our results present new perspectives into the complex nature of the HLA class II system and will aid future immunological studies in characterizing the full breadth of potential CD4(+) T cell epitopes relevant in health and disease.
引用
收藏
页码:1412 / 1423
页数:12
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