Exploring the MHC-peptide matrix of central tolerance in the human thymus

TY - JOUR

T1 - Exploring the MHC-peptide matrix of central tolerance in the human thymus

AU - Adamopoulou, Eleni

AU - Tenzer, Stefan

AU - Hillen, Nina

AU - Klug, Paula

AU - Rota, Ioanna A

AU - Tietz, Silvia

AU - Gebhardt, Madlen

AU - Stevanovic, Stefan

AU - Schild, Hansjörg

AU - Tolosa, Eva

AU - Melms, Arthur

AU - Stoeckle, Christina

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Ever since it was discovered that central tolerance to self is imposed on developing T cells in the thymus through their interaction with self-peptide major histocompatibility complexes on thymic antigen-presenting cells, immunologists have speculated about the nature of these peptides, particularly in humans. Here, to shed light on the so-far unknown human thymic peptide repertoire, we analyse peptides eluted from isolated thymic dendritic cells, dendritic cell-depleted antigen-presenting cells and whole thymus. Bioinformatic analysis of the 842 identified natural major histocompatibility complex I and II ligands reveals significant cross-talk between major histocompatibility complex-class I and II pathways and differences in source protein representation between individuals as well as different antigen-presenting cells. Furthermore, several autoimmune- and tumour-related peptides, from enolase and vimentin for example, are presented in the healthy thymus. 302 peptides are directly derived from negatively selecting dendritic cells, thus providing the first global view of the peptide matrix in the human thymus that imposes self-tolerance in vivo.

AB - Ever since it was discovered that central tolerance to self is imposed on developing T cells in the thymus through their interaction with self-peptide major histocompatibility complexes on thymic antigen-presenting cells, immunologists have speculated about the nature of these peptides, particularly in humans. Here, to shed light on the so-far unknown human thymic peptide repertoire, we analyse peptides eluted from isolated thymic dendritic cells, dendritic cell-depleted antigen-presenting cells and whole thymus. Bioinformatic analysis of the 842 identified natural major histocompatibility complex I and II ligands reveals significant cross-talk between major histocompatibility complex-class I and II pathways and differences in source protein representation between individuals as well as different antigen-presenting cells. Furthermore, several autoimmune- and tumour-related peptides, from enolase and vimentin for example, are presented in the healthy thymus. 302 peptides are directly derived from negatively selecting dendritic cells, thus providing the first global view of the peptide matrix in the human thymus that imposes self-tolerance in vivo.

KW - Adolescent

KW - Antigen Presentation

KW - Antigen-Presenting Cells

KW - Antigens, CD11c

KW - Autoantigens

KW - Autoimmunity

KW - Central Tolerance

KW - Child, Preschool

KW - Dendritic Cells

KW - Epitopes

KW - Female

KW - Histocompatibility Antigens Class I

KW - Histocompatibility Antigens Class II

KW - Humans

KW - Infant

KW - Ligands

KW - Major Histocompatibility Complex

KW - Male

KW - Myeloid Cells

KW - Peptides

KW - T-Lymphocytes

KW - Thymus Gland

U2 - 10.1038/ncomms3039

DO - 10.1038/ncomms3039

M3 - SCORING: Journal article

C2 - 23783831

VL - 4

SP - 2039

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

ER -