Bicarbonate transport and intracellular pH homeostasis as a checkpoint for T‑cell function in acidic tissues

T cells must function in tissues where extracellular pH (pHe) becomes acidic in infection, inflammation and tumours – an environment that suppresses effector function even when antigen recognition is intact. As activation-driven glycolysis generates intracellular acid load, maintaining intracellular pH (pHi) may be a key bottleneck for tissue immunity. This programme will test whether sodium-coupled bicarbonate co-transporters (SLC4A7/NBCn1 and SLC4A10/NBCn2), acting with lactate/proton export and carbonic anhydrases, form an “immune acid-tolerance module” that sustains pH homeostasis, metabolism and effector programmes in human T cell subsets adapted to harsh environments, such as mucosal-associated invariant T (MAIT) and tissue-resident T cells. I will: (i) define causal transport mechanisms using live-cell pH imaging, genetic and pharmacological perturbation, and single-cell multi-omics under controlled acid stress; (ii) map acidic immune niches in human tissues and derive transferable pH-adaptation signatures using spatial transcriptomics and computational inference; and (iii) test proof-of-concept engineering strategies to enhance pH resilience in tissue-relevant models, including organoids and CAR-T systems. Outputs will include validated assays, an atlas of acidic immune niches, and prioritised targets for tuning immunity in acidic microenvironments. Keywords: intracellular pH, bicarbonate transport, SLC4A7, SLC4A10, MAIT cells, acid-base physiology, tissue immunity, spatial transcriptomics.