Proteasomes shape the repertoire of T cells participating in antigen-specific immune responses.
Differences in the cleavage specificities of constitutive proteasomes and immunoproteasomes significantly affect the generation of MHC class I ligands and therefore the activation of CD8-positive T cells. Based on these findings, we investigated whether proteasomal specificity also influences CD8-positive T cells during thymic selection by peptides derived from self proteins. We find that one of the self peptides responsible for positive selection of ovalbumin-specific OT-1 T cells, which is derived from the f-actin capping protein (Cpalpha1), is efficiently generated only by immunoproteasomes. Furthermore, OT-1 mice backcrossed onto low molecular mass protein 7 (LMP7)-deficient mice show a 50% reduction of OT-1 cells. This deficiency is also observed after transfer of BM from OT-1 mice in LMP7-deficient mice and can be corrected by the injection of the Cpalpha1 peptide. Interestingly, WT and LMP7-deficient mice mount comparable immune responses to the ovalbumin-derived epitope SIINFEKL. However, their cytotoxic T lymphocytes (CTL) differ in the use of T cell receptor Vbeta genes. CTL derived from WT mice use Vbeta8 or Vbeta5 (the latter is also used by OT-1 cells), whereas SIINFEKL-specific CTL from LMP7-deficient mice are exclusively Vbeta8-positive. Taken together, our experiments provide strong evidence that proteasomal specificity shapes the repertoire of T cells participating in antigen-specific immune responses.
Osterloh
Philipp
P
Institute of Immunology, University of Mainz, Obere Zahlbacherstrasse 67, 55131 Mainz, Germany.
Linkemann
Kathrin
K
Tenzer
Stefan
S
Rammensee
Hans-Georg
HG
Radsak
Markus P
MP
Busch
Dirk H
DH
Schild
Hansjörg
H
D051344:Actin Capping Proteins / Q000737:chemistry / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D012641:Selection, Genetic; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
D051344:Actin Capping Proteins; D000941:Antigens; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D011947:Receptors, Antigen, B-Cell; D010047:Ovalbumin; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex