Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands [corrected].
While much is known about intracellular signaling events in T cells when T cell receptors (TCRs) are engaged, the mechanism by which signaling is initiated is unclear. We have constructed defined oligomers of soluble antigen-major histocompatibility complex (MHC) molecules, the natural ligands for the TCR. Using these to stimulate specific T cells in vitro, we find that agonist peptide/MHC ligands are nonstimulatory as monomers and minimally stimulatory as dimers. Similarly, a partial-agonist ligand is very weakly active as a tetramer. In contrast, trimeric or tetrameric agonist ligands that engage multiple TCRs for a sustained duration are potent stimuli. Ligand-driven formation of TCR clusters seems required for effective activation and helps to explain the specificity and sensitivity of T cells.
Boniface
J J
JJ
Department of Microbiology and Immunology, Stanford University, California 94305, USA.
Rabinowitz
J D
JD
Wülfing
C
C
Hampl
J
J
Reich
Z
Z
Altman
J D
JD
Kantor
R M
RM
Beeson
C
C
McConnell
H M
HM
Davis
M M
MM
D000595:Amino Acid Sequence; D000818:Animals; D015374:Biosensing Techniques; D020013:Calcium Signaling; D019281:Dimerization; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011487:Protein Conformation; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D006649:Histocompatibility Antigens; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell