Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity.
Alphabeta T lymphocytes are able to detect even a single peptide-major histocompatibility complex (MHC) on the surface of an antigen-presenting cell. This is despite clear evidence, at least with CD4+ T cells, that monomeric ligands are not stimulatory. In an effort to understand how this remarkable sensitivity is achieved, we constructed soluble peptide-MHC heterodimers in which one peptide is an agonist and the other is one of the large number of endogenous peptide-MHCs displayed by presenting cells. We found that some specific combinations of these heterodimers can stimulate specific T cells in a CD4-dependent manner. This activation is severely impaired if the CD4-binding site on the agonist ligand is ablated, but the same mutation on an endogenous ligand has no effect. These data correlate well with analyses of lipid bilayers and cells presenting these ligands, and indicate that the basic unit of helper T cell activation is a heterodimer of agonist peptide- and endogenous peptide-MHC complexes, stabilized by CD4.
Krogsgaard
Michelle
M
The Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Li
Qi-Jing
QJ
Sumen
Cenk
C
Huppa
Johannes B
JB
Huse
Morgan
M
Davis
Mark M
MM
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016466:CHO Cells; D020013:Calcium Signaling; D006224:Cricetinae; D019281:Dimerization; D006680:HLA Antigens / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008051:Lipid Bilayers / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D012680:Sensitivity and Specificity
D006680:HLA Antigens; D007376:Interleukin-2; D008051:Lipid Bilayers; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta