TY - JOUR
T1 - 2D TCR-pMHC-CD8 kinetics determines T-cell responses in a self-antigen-specific TCR system
AU - Liu, Baoyu
AU - Zhong, Shi
AU - Malecek, Karolina
AU - Johnson, Laura A.
AU - Rosenberg, Steven A.
AU - Zhu, Cheng
AU - Krogsgaard, Michelle
PY - 2014/1
Y1 - 2014/1
N2 - Two-dimensional (2D) kinetic analysis directly measures molecular interactions at cell-cell junctions, thereby incorporating inherent cellular effects. By comparison, three-dimensional (3D) analysis probes the intrinsic physical chemistry of interacting molecules isolated from the cell. To understand how T-cell tumor reactivity relates to 2D and 3D binding parameters and to directly compare them, we performed kinetic analyses of a panel of human T-cell receptors (TCRs) interacting with a melanoma self-antigen peptide (gp100209-217) bound to peptide-major histocompatibility complex in the absence and presence of co-receptor CD8. We found that while 3D parameters are inadequate to predict T-cell function, 2D parameters (that do not correlate with their 3D counterparts) show a far broader dynamic range and significantly improved correlation with T-cell function. Thus, our data support the general notion that 2D parameters of TCR-peptide-major histocompatibility complex-CD8 interactions determine T-cell responsiveness and suggest a potential 2D-based strategy to screen TCRs for tumor immunotherapy.
AB - Two-dimensional (2D) kinetic analysis directly measures molecular interactions at cell-cell junctions, thereby incorporating inherent cellular effects. By comparison, three-dimensional (3D) analysis probes the intrinsic physical chemistry of interacting molecules isolated from the cell. To understand how T-cell tumor reactivity relates to 2D and 3D binding parameters and to directly compare them, we performed kinetic analyses of a panel of human T-cell receptors (TCRs) interacting with a melanoma self-antigen peptide (gp100209-217) bound to peptide-major histocompatibility complex in the absence and presence of co-receptor CD8. We found that while 3D parameters are inadequate to predict T-cell function, 2D parameters (that do not correlate with their 3D counterparts) show a far broader dynamic range and significantly improved correlation with T-cell function. Thus, our data support the general notion that 2D parameters of TCR-peptide-major histocompatibility complex-CD8 interactions determine T-cell responsiveness and suggest a potential 2D-based strategy to screen TCRs for tumor immunotherapy.
KW - 2D kinetics
KW - Micropipette adhesion frequency assay
KW - T-cell activation
KW - Thermal fluctuation assay
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U2 - 10.1002/eji.201343774
DO - 10.1002/eji.201343774
M3 - Article
C2 - 24114747
AN - SCOPUS:84892469907
SN - 0014-2980
VL - 44
SP - 239
EP - 250
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 1
ER -