Allosteric Regulation of Early T-cell Receptor Signaling by Potassium

Roy, Swarnendu (2025) Allosteric Regulation of Early T-cell Receptor Signaling by Potassium. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Swarnendu Roy (16IP014)) 16IP014.pdf - Submitted Version Restricted to Repository staff only Download (54MB)

Abstract

T-cell Receptors (TCR) discriminate between self and non-self antigens from billions of different antigens. They achieve this remarkable specificity through a kinetic proofreading mechanism consisting of a spatiotemporal web of diverse kinases in the early TCR Signaling. Such a high level of regulation is needed to prevent hyperactivation, the failure of which is often causes autoimmune disorders. At the same time, silencing of the TCR response allows pathogens and cancerous cells to escape immune surveillance. Once the TCR complex is formed, it initiates signaling by assembling the two tyrosine kinases, Lck and ZAP-70. Propagation of downstream signaling requires phosphorylation of multiple tyrosine residues in adapter modules like CD3ζ and LAT. Our recent studies suggest that a thermodynamic penally in the early TCR activation may a key step in proofreading and determining the specificity of TCR signaling, preventing autonomous ZAP-70 activation. How is TCR proofreading breached by cancer cells? Recent studies indicate that ionic imbalance in a tumor microenvironment inactivates T-cells, helping tumor to evade immune response. This thesis will present a mechanism explaining how perturbations in potassium ion flux may modulate T-cell signaling. We observed that alterations in cellular ion flux interfere with the downstream propagation of early TCR signaling.

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