CD8+ cytotoxic T lymphocyte activation by soluble major histocompatibility complex-peptide dimers.
CD8+ cytotoxic T lymphocyte (CTL) can recognize and kill target cells that express only a few cognate major histocompatibility complex class I-peptide (pMHC) complexes. To better understand the molecular basis of this sensitive recognition process, we studied dimeric pMHC complexes containing linkers of different lengths. Although dimers containing short (10-30-A) linkers efficiently bound to and triggered intracellular calcium mobilization and phosphorylation in cloned CTL, dimers containing long linkers (> or = 80 A) did not. Based on this and on fluorescence resonance energy transfer experiments, we describe a dimeric binding mode in which two T cell receptors engage in an anti-parallel fashion two pMHC complexes facing each other with their constant domains. This binding mode allows integration of diverse low affinity interactions, which increases the overall binding and, hence, the sensitivity of antigen recognition. In proof of this, we demonstrated that pMHC dimers containing one agonist and one null ligand efficiently activate CTL, corroborating the importance of endogenous pMHC complexes in antigen recognition.
Cebecauer
Marek
M
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, 1066 Epalinges, Switzerland.
Guillaume
Philippe
P
Mark
Silke
S
Michielin
Olivier
O
Boucheron
Nicole
N
Bezard
Michael
M
Meyer
Bruno H
BH
Segura
Jean-Manuel
JM
Vogel
Horst
H
Luescher
Immanuel F
IF
D000595:Amino Acid Sequence; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D005456:Fluorescent Dyes; D006801:Humans; D047468:Immunoprecipitation; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*
D005456:Fluorescent Dyes; D010455:Peptides