Toward contextualizing receptor-ligand interactions in T cells and macrophages

T cells;CD4;TCR;pMHC;Affinity;Kinetics;On rate;Off rate;Micropipette;Biomembrane force probe;Adhesion;Activation;Macrophages;TLR4;LPS;Reactive oxygen species;ROS

Nik Rushdi, Nik Muaz ; Zhu, Cheng Chen, Antony Biomedical Engineering (Joint GT/Emory Department) Brown, Lou Ann Kemp, Melissa Salaita, Khalid ; Zhu, Cheng

University:Georgia Institute of Technology

Department:Biomedical Engineering (Joint GT/Emory Department)

关键词: T cells;    CD4;    TCR;    pMHC;    Affinity;    Kinetics;    On rate;    Off rate;    Micropipette;    Biomembrane force probe;    Adhesion;    Activation;    Macrophages;    TLR4;    LPS;    Reactive oxygen species;    ROS;   

Others  :  https://smartech.gatech.edu/bitstream/1853/62676/1/NIKRUSHDI-DISSERTATION-2019.pdf

美国|英语

来源: SMARTech Repository

【 摘 要 】

T cell mediated immune response to pathogens is triggered by the T cell receptor (TCR) engaging with peptide-major histocompatibility complex (pMHC), which can be facilitated by the CD4 coreceptor. However, detecting CD4-pMHC binding has been elusive. To address this limitation, the first aim of this thesis was to characterize CD4-pMHC binding and mathematically model trimolecular cooperativity. Herein, the complete set of CD4-pMHC kinetics was experimentally determined and these results were used to develop analytical solutions for trimolecular cooperativity. As T cells travel to sites of inflammation, the trimolecular complex is exposed reactive oxygen species (ROS). The dual-role of ROS has long convoluted study of its effect on immune cells. Therefore, the second aim of this thesis was to monitor TCR-pMHC binding in response to ROS in real-time, in order to deconvolute how the many molecules involved in binding are each affected. It was concluded that TCR-pMHC binding is weakened due to the disruption of the trimolecular complex by ROS. Similar to T cells, the macrophage TLR4 receptor requires other surface receptors to robustly recognize its ligand, and the relationship between ROS and macrophage function is mired with conflicting results. Correspondingly, the framework developed in the first two aims of this thesis was applied to a third aim which sought to understand how macrophage function can be both enhanced and impaired by ROS. These data suggest that unlike T cells, macrophage function is diverse in its regulation. Overall, by introducing biophysical and biochemical contexts to receptor-ligand interactions in tandem, a better understanding of how our immune system specifically and sensitively detects pathogens was achieved.