Intestinal tissue-resident T cell activation depends on metabolite availability

The metabolic capacity of many cells is tightly regulated and can adapt to changes in metabolic resources according to environmental changes. Tissue-resident memory (T_RM) CD8⁺ T cells are one of the most abundant T cell populations and offer rapid protection against invading pathogens, especially at the epithelia. T_RM cells metabolically adapt to their tissue niche, such as the intestinal epithelial barrier. In the small intestine, the types of T_RM cells are intraepithelial lymphocytes (IELs), which contain high levels of cytotoxic molecules and express activation markers, suggesting a heightened state of activation. We hypothesize that the tissue environment may determine IEL activity. We show that IEL activation, in line with its semiactive status, is metabolically faster than circulating CD8⁺ T cells. IEL glycolysis and oxidative phosphorylation (OXPHOS) are interdependently regulated and are dependent on rapid access to metabolites from the environment. IELs are restrained by local availability of metabolites, but, especially, glucose levels determine their activity. Importantly, this enables functional control of intestinal T_RM cells by metabolic means within the fragile environment of the intestinal epithelial barrier.