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Abstract
Noncognate or self peptide-MHC (pMHC) ligands productively interact with T-cell receptor (TCR) and are always in a large access over the cognate pMHC on the surface of antigen presenting cells. We assembled soluble cognate and noncognate pMHC class I (pMHC-I) ligands at designated ratios on various scaffolds into oligomers that mimic pMHC clustering and examined how multivalency and density of the pMHCs in model clusters influences the binding to live CD8 T cells and the kinetics of TCR signaling. Our data demonstrate that the density of self pMHC-I proteins promotes their interaction with CD8 co-receptor, which plays a critical role in recognition of a small number of cognate pMHC-I ligands. This suggests that MHC clustering on live target cells could be utilized as a sensitive mechanism to regulate T cell responsiveness.
Highlights
It has been proposed that T-cell responses are regulated by the number of pMHC ligands, and by the spatial arrangement and the density of the ligands on the surface of APC or target cells [1,2]
To understand a unique ability of noncognate pMHC class I (pMHC-I) displayed on quantum dots (QD) to bind vigorously to the surface of live CD8+ T cells [8], we first compared the binding of cognate and noncognate pMHC-I/QD with that of the same pMHC-I ligands assembled on Streptavidin scaffold into the tetramer
The binding of noncognate pMHC-I/QD was evident at various concentrations indicating that the ability of noncognate pMHC/QD to bind to the T-cell surface was an intrinsic property of pMHC-I/QD conjugates as opposed to the tetramer (Fig. S1)
Summary
It has been proposed that T-cell responses are regulated by the number of pMHC ligands, and by the spatial arrangement and the density of the ligands on the surface of APC or target cells [1,2]. To demonstrate directly cooperation between cognate and noncognate pMHC ligands several model systems have been tested, in which the pMHC proteins were assembled into oligomers containing cognate and noncognate pMHC [6,7,8,9]. We have previously utilized fluorescent nanoparticles quantum dots (QD) as a scaffold to assembled pMHC-I proteins with various biological activities at designated ratios and have demonstrated that cognate and noncognate pMHC ligands efficiently cooperate in the binding to CD8+ CTL and the induction of TCR-mediated Ca2+ signaling [8]. We compared QD with two other scaffolds, Streptavidin and dextran, to vary multivalency and density of pMHC-I proteins assembled on these scaffolds and to study how these parameters influence the binding to live CD8+ T cells and the kinetics of TCR signaling
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