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) CD8 T cells are one of the most abundant T cell populations and offer rapid protection against invading pathogens, especially at the epithelia. T cells metabolically adapt to their tissue niche, such as the intestinal epithelial barrier.

Heterogeneity of tissue resident memory T cells.

Non-lymphoid organs, in mice and humans, contain CD8 tissue-resident memory T (T) cells. They play important roles in tissue homoeostasis as well as defence against infections and cancer. T cells have common characteristics that enables their tissue residency and function.

The fungal Clitocybe nebularis lectin binds distinct cell surface glycoprotein receptors to induce cell death selectively in Jurkat cells.

Clitocybe nebularis lectin (CNL) is a GalNAcβ1-4GlcNAc-binding lectin that exhibits an antiproliferative effect exclusively on the Jurkat leukemic T cell line by provoking homotypic aggregation and dose-dependent cell death. Cell death of Jurkat cells exhibited typical features of early apoptosis, but lacked the activation of initiating and executing caspases. None of the features of CNL-induced cell death were effectively blocked with the pan-caspase inhibitor or different cysteine peptidase inhibitors.

Regulation of Oxygen Homeostasis at the Intestinal Epithelial Barrier Site.

The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function.

Type 1 T cells promote the generation of CD8 tissue-resident memory T cells.

Tissue-resident memory T (T) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of T cells are incompletely understood. Here we show that type 1 regulatory T (T) cells, which express the transcription factor T-bet, promote the generation of CD8 T cells. The absence of T-bet-expressing type 1 T cells reduces the presence of T cells in multiple tissues and increases pathogen burden upon infectious challenge.

Dynamic Metabolic State of Tissue Resident CD8 T Cells.

In the past years, there have been significant advances in the understanding of how environmental conditions alone or in conjunction with pathogen invasion affect the metabolism of T cells, thereby influencing their activation, differentiation, and longevity. Detailed insights of the interlinked processes of activation and metabolism can contribute to major advances in immunotherapies. Naive and memory T cells circulate the body.

Metabolic wiring of murine T cell and intraepithelial lymphocyte maintenance and activation.

Adaptive immunity critically depends on cell migration combined with clonal selection and rapid expansion of rare lymphocytes recognising their cognate antigen in secondary lymphoid organs. It has since become apparent that large populations of T cells are maintained in tissues, which do not migrate throughout the body and do not require clonal expansion. Murine intraepithelial lymphocytes (IELs), located in the skin and small intestines, are maintained in a state of semi-activation, in marked contrast to the quiescent condition naive and memory lymphocytes are kept in.

Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes.

Epithelial-resident T lymphocytes, such as intraepithelial lymphocytes (IELs) located at the intestinal barrier, can offer swift protection against invading pathogens. Lymphocyte activation is strictly regulated because of its potential harmful nature and metabolic cost, and most lymphocytes are maintained in a quiescent state. However, IELs are kept in a heightened state of activation resembling effector T cells but without cytokine production or clonal proliferation.

Intestinal Barrier Interactions with Specialized CD8 T Cells.

The trillions of microorganisms that reside in the gastrointestinal tract, essential for nutrient absorption, are kept under control by a single cell barrier and large amounts of immune cells. Intestinal epithelial cells (IECs) are critical in establishing an environment supporting microbial colonization and immunological tolerance. A large population of CD8 T cells is in direct and constant contact with the IECs and the intraepithelial lymphocytes (IELs).

Cystatin F regulates proteinase activity in IL-2-activated natural killer cells.

Cystatin F is a unique member of the cystatin family of cysteine protease inhibitors, which is synthesized as an inactive dimer and it is activated by N-terminal cleavage in the endolysosomes. It is expressed in the cells of the immune system: myeloid cells and the cells involved in target cell killing: natural killer (NK) cells and cytotoxic T cells (CTLs). Upon activation of the NK cells with interleukin 2 (IL-2), cystatin F was found upregulated and co-localized in cytotoxic granules with cathepsin C (CatC) and CatV.

Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L.

The pore-forming protein perforin is synthesized as an inactive precursor in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and becomes active when a short C-terminal peptide is cleaved within acidic lysosome-like cytotoxic granules. Although it was shown more than a decade ago that this cleavage is pH dependent and can be inhibited by the generic cysteine cathepsin inhibitor E-64d, no protease capable of processing the perforin C terminus has been identified. Neither is it known whether a single protease is responsible or the processing has inbuilt redundancy.

Increased nucleolar localization of SpiA3G in classically but not alternatively activated macrophages.

Macrophages play a key role in innate immune response to pathogens and in tissue homeostasis, inflammation and repair. A serpin A3G (SpiA3G) is highly induced in classically activated macrophages. We show increased localization of SpiA3G in the nucleolus and co-localization with cathepsin L, upon classical, but not alternative activation of macrophages.

Stefin B interacts with histones and cathepsin L in the nucleus.

Stefin B (cystatin B) is an endogenous inhibitor of cysteine proteinases localized in the nucleus and the cytosol. Loss-of-function mutations in the stefin B gene (CSTB) gene were reported in patients with Unverricht-Lundborg disease (EPM1). We have identified an interaction between stefin B and nucleosomes, specifically with histones H2A.