Investigating the Role of Intracellular Potassium in Early T Cell Response

Sinha, Anushka (2025) Investigating the Role of Intracellular Potassium in Early T Cell Response. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Anushka Sinha (20MS029)) 20MS029_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (1MB)

Abstract

The tumour microenvironment has been known to dampen the effector function of T cells and negatively impact the TCR signalling. One of the reasons for this is the high extracellular potassium ion content in the TME. Necrotic tumour cells release their intracellular K+ content, thus raising the ionic concentration in the TME. This high K+ content decouples the TCR-antigen binding from the downstream protein activation. The protein tyrosine kinase ZAP70, a major regulator of this signalling pathway, has been proven to be affected by this high extracellular K+ concentration. Here, we have expanded on the relationship between ZAP70 and this ion flux concerning the TCR signalling. It is also imperative to know whether ZAP70 itself governs K+ and Ca2+ flux in T cells for which we have estimated the ion signalling in high [K+] in ZAP70 deficient and B cells. Our studies show a relatively constant signalling pattern in these cells under all [K+], which suggests a certain degree of interdependency of ZAP70 activation and a sustained ion flux. Loss of the aromatic stacking network in the tSH2 domains like that due to the W165C mutation alters ZAP70 recruitment to its ligand, ITAM. Therefore, it also becomes important for us to study the changes in the binding kinetics of this mutated ZAP70 to the ITAM. Overall, our discoveries uncover that intracellular K⁺ efflux is more than a bystander but an essential driving force of ZAP70 activation and that ZAP70, in turn, synchronizes the early ion flux critical to productive T cell signalling. Such ion‑kinase cross-talk may be a novel target for reversing T cell functionality in immunosuppressive TMEs.

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