Agonist/endogenous peptide–MHC heterodimers drive T cell activation and sensitivity

Michelle Krogsgaard, Qi-jing Li, Cenk Sumen, Johannes B. Huppa, Morgan Huse and Mark M. Davis ()
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Michelle Krogsgaard: The Department of Microbiology and Immunology, and
Qi-jing Li: The Department of Microbiology and Immunology, and
Cenk Sumen: The Department of Microbiology and Immunology, and
Johannes B. Huppa: The Department of Microbiology and Immunology, and
Morgan Huse: The Department of Microbiology and Immunology, and
Mark M. Davis: The Department of Microbiology and Immunology, and

Nature, 2005, vol. 434, issue 7030, 238-243

Abstract: Abstract αβ T lymphocytes are able to detect even a single peptide–major histocompatibility complex (MHC) on the surface of an antigen-presenting cell1,2. This is despite clear evidence, at least with CD4+ T cells, that monomeric ligands are not stimulatory3,4. 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.

Date: 2005
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DOI: 10.1038/nature03391

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