Weak agonist self-peptides promote selection and tuning of virus-specific T cells.
Recent progress has begun to define the interactions and signaling pathways that are triggered during positive selection. To identify and further examine self-peptides that can mediate positive selection, we searched a protein-database to find peptides that have minimal homology with the viral peptide (p33) that activates a defined P14 transgenic TCR. We identified four peptides that could bind the restriction element H-2D(b) and induce proliferation of P14 transgenic splenocytes at high concentration. Two of the four peptides (DBM and RPP) were able to positively select the virus-specific TCR in fetal thymic organ culture but were unable to induce clonal deletion. Reverse-phase HPLC and mass spectrometry demonstrated that these peptides were presented by H-2D(b) molecules on thymic epithelial cell lines. We also examined whether the selecting ligands altered T cell responsiveness in vitro. DBM-selected T cells lost their ability to respond to the positively selecting ligand DBM, whereas RPP-selected T cells only retained their ability to respond to high concentrations of RPP. These results demonstrate that self-peptides that mediate positive selection can differentially "tune" the activation threshold of T cells and alter the functional repertoire of T cells.
Saibil
Samuel D
SD
Departments of Medical Biophysics and Immunology, University Health Network, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
Ohteki
Toshiaki
T
White
Forest M
FM
Luscher
Mark
M
Zakarian
Arsen
A
Elford
Alisha
A
Shabanowitz
Jeffery
J
Nishina
Hiroshi
H
Hugo
Patrice
P
Penninger
Josef
J
Barber
Brian
B
Hunt
Donald F
DF
Ohashi
Pamela S
PS
D000595:Amino Acid Sequence; D000818:Animals; D004299:Dopamine beta-Hydroxylase / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D004299:Dopamine beta-Hydroxylase; D066246:ErbB Receptors