Dr. Cheng Zhu, Adviser (Dept. of Biomedical Engineering. Georgia Institute of Technology)
Dr. Andres Garcia (Dept. of Mechanical Engineering. Georgia Institute of Technology)
Dr. JC Gumbart (Dept. of Physics, Georgia Institute of Technology)
Dr. Arash Grakoui (Dept. of Medicine, Division of Infectious Diseases, Emory University)
Dr. Jizhong Lou (Institute of Biophysics, Chinese Academy of Sciences)
Principles for molecular recognition of antigens and activation of CD3 signaling domains by the T-Cell Receptor and the mechanobiology of PD-1 Receptor: A Molecular Perspective.
There are continually strong demands in understanding the principles for molecular recognition of antigens and activation of T cells because of their broad implications in immunology and the benefits in cancer immunotherapy. Antigen processing and presentation was extensively studied; however how TCR recognizes pMHC and then activates the signaling machinery is not understood. This question has puzzled immunologist for decades and understanding if there exists a mechanism genetically encoded to propagate information read from the TCR distal-membrane binding site to inside the cell is considered the holy grail of molecular immunology. It is believed that TCRs mediate T cell activation by connecting their dimeric αβ chains with CD3ϵγ, CD3ϵδ, and CD3ζζ subunits using an "unknown mechanism" and the Cβ FG loop in TCRs is regarded as very important since its removal severely affects T cell activation and development.
The first part of this thesis studied the force response of a TCR reading out a pMHC in the context of viral infection and explained how information encoded in the peptide is decoded by the TCR. For the first time, it is demonstrated that TCRs are capable of forming "in silico" catch bonds as they do in experiments. It is explained the characteristics and requirements of catch bonds in antigen recognition and how mutant epitopes abolish it. It is shown that TCR modulate the peptide conformation by using highly conserved residues in MHCs. Finally it is proposed the molecular mechanism of how the TCR reads a viral featureless pMHCs: "RA14 uses a molecular lever to form an in "in silico" catch bond and recognize antigenic peptides”. The second part established the principles for molecular recognition of antigens and the mechanical activation of signaling domains by the TCR. It is proposed that the decoding process and early intracellular signaling are connected by conformational changes in the TCR. The TCR interaction with either the pMHC and CD3 domains are hardwire on its structural dynamics. TCRs are not rigid entities, as currently thought, but they are deformable proteins and mechanical forces modulate their conformations. The ability of the TCR to deform without releasing the pMHC and to transform linear force into rotational torque is the key to understand this molecular mechanism. It is explained the role of the CβFG loop in activating the CD3 signaling domains.
Lastly it is described the molecular mechanism of how force regulates the interaction between PD-1 and its PD-Ligands. It is show how force fosters the PD-1 and PD-Ligand interaction and allows PD-1 to experience positional, orientational, and conformational changes to identify a new hot spot that it is away from the initial binding interface. The main characteristic of the hot spot is to prolongs the bond-life time by producing forced-induced H-bonds. A detailed analysis of the interaction between PD-1 and its ligands is provided.