TCR triggering by pMHC ligands tethered on surfaces via poly(ethylene glycol) depends on polymer length.
Antigen recognition by T cells relies on the interaction between T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) at the interface between the T cell and the antigen presenting cell (APC). The pMHC-TCR interaction is two-dimensional (2D), in that both the ligand and receptor are membrane-anchored and their movement is limited to 2D diffusion. The 2D nature of the interaction is critical for the ability of pMHC ligands to trigger TCR. The exact properties of the 2D pMHC-TCR interaction that enable TCR triggering, however, are not fully understood. Here, we altered the 2D pMHC-TCR interaction by tethering pMHC ligands to a rigid plastic surface with flexible poly(ethylene glycol) (PEG) polymers of different lengths, thereby gradually increasing the ligands' range of motion in the third dimension. We found that pMHC ligands tethered by PEG linkers with long contour length were capable of activating T cells. Shorter PEG linkers, however, triggered TCR more efficiently. Molecular dynamics simulation suggested that shorter PEGs exhibit faster TCR binding on-rates and off-rates. Our findings indicate that TCR signaling can be triggered by surface-tethered pMHC ligands within a defined 3D range of motion, and that fast binding rates lead to higher TCR triggering efficiency. These observations are consistent with a model of TCR triggering that incorporates the dynamic interaction between T cell and antigen-presenting cell.
Department of Biomedical Research, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, United States of America.
Zhengyu
Z
Ma
Department of Chemistry, Yeshiva University, New York, New York, United States of America.
David N
DN
LeBard
Department of Chemistry, College of Staten Island, City University of New York, Staten Island, New York, United States of America.
Sharon M
SM
Loverde
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Kim A
KA
Sharp
Institute for Computational Molecular Science and Department of Chemistry, Temple University, Philadelphia, Pennsylvania, United States of America.
Michael L
ML
Klein
Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Dennis E
DE
Discher
Department of Pediatrics, Nemours Children's Hospital, Orlando, Florida, United States of America; Department of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, Florida, United States of America.
Terri H
TH
Finkel
D000818:Animals; D006649:Histocompatibility Antigens / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D008970:Molecular Weight; D010455:Peptides / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013499:Surface Properties
D006649:Histocompatibility Antigens; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011092:Polyethylene Glycols