T cells rely on bicarbonate to regulate their internal acidity, and a specific bicarbonate transporter called SLC4A10 is found only on a subset of immune cells known as MAIT cells. This matters because T cells must function in acidic environments—such as tumours—where pH regulation becomes critical for their survival and activity. The role of bicarbonate transport in T cell function is poorly understood, and this project aims to fill that gap by showing how SLC4A10 helps MAIT cells manage pH and sustain the glycolysis they need for immune responses. If the research succeeds, it could improve CAR-T cell therapy, a treatment where a patient’s own T cells are engineered to attack cancer. Understanding how bicarbonate transport supports T cell function in acidic tumour microenvironments might make these therapies more effective. The work is fundamental science—it asks how a basic cellular process (pH regulation) controls immune cell behaviour. Similar fundamental research on ion transport has previously led to breakthroughs in drug design for cystic fibrosis and kidney disease. Deeper knowledge of SLC4A10 could eventually inform new strategies to boost T cell activity in cancer or chronic infections.
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Intracellular pH (pHi) homeostasis is vital for cellular functions, including metabolism and signalling. SLC4 sodium-bicarbonate cotransporters (NBCs) are important bicarbonate importers, highly conserved throughout evolution. T cells in tissues are highly sensitive to local pH - regulation via NBCs is critical, although poorly explored. Mucosal-associated invariant T (MAIT) cells, an abundant T-cell subset in blood, represent an important, tractable model for tissue-associated T cells. I have confirmed that, uniquely amongst T cells, MAIT cells express a distinct NBC, SLC4A10. This provides an opportunity to understand pH-driven homeostasis of T cells. I have shown that MAIT cells are dependent on bicarbonate transport for pHi homeostasis, with a small-molecule inhibitor (S0859) impacting effector functions in response to vaccines. Given the importance of glycolysis for MAIT cell effector functions, which inherently affects pHi, I hypothesise that SLC4A10 facilitates bicarbonate-dependent processes essential for T cell glycolysis and function, particularly in acidotic microenvironments (e.g. tumours). This study will provide key insights into how T cell function is regulated via bicarbonate transport, which will be relevant to T cell tissue memory and CAR-T cell therapy. Aims and Objectives: 1. Characterise the impact of bicarbonate transport on T cell pHi and function. 2. Specifically assess the role of SLC4A10 in MAIT cell pHi regulation using small-molecule inhibitors, transcriptional profiling, and CRISPR-Cas9 gene editing. Methodology: I will use ex vivo T cells and in vitro cultured lines and clones, live cell imaging, gene editing, and functional assays, to understand potential physiological roles of SLC4A10 in T cell regulation.
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