Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos.

CD4 regulatory T (T) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences T cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched.

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8 T cell expression of GOT1, a central enzyme in the malate shuttle.

Differential Effects of RNA-Dependent RNA Polymerase 6 (RDR6) Silencing on New and Old World Begomoviruses in .

RNA-dependent RNA polymerases (RDRs) are key players in the antiviral defence mediated by RNA silencing in plants. RDR6 is one of the major components of the process, regulating the infection of certain RNA viruses. To better clarify its function against DNA viruses, we analyzed the effect of RDR6 inactivation (RDR6i) in plants on two phloem-limited begomoviruses, the bipartite Abutilon mosaic virus (AbMV) and the monopartite tomato yellow leaf curl Sardinia virus (TYLCSV).

Regulatory T cell-derived interleukin-15 promotes the diversity of immunological memory.

While the immunosuppressive function of regulatory T (Treg) cells has been extensively studied, their immune-supportive roles have been less well investigated. Using a lymphocytic choriomeningitis virus (LCMV) Armstrong infection mouse model, we found that Treg cell-derived interleukin (IL)-15 is required for long-term maintenance of the KLRG1 IL-7Rα CD62L terminal effector memory CD8 T (tTEM) cell subset, but dispensable for the suppressive function of Treg cells themselves. In contrast, deletion of Il15 from other sources, including myeloid cells and muscles, did not affect the composition of the memory CD8 T cell pool.

Rgs16 promotes antitumor CD8 T cell exhaustion.

T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (T) cell differentiation are known, comparatively little is known about the regulators of T cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed T cell survival in tumors.

CD8 agonism functionally activates memory T cells and enhances antitumor immunity.

Memory CD8 T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8 T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody-mediated activation of memory CD8 T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell-mediated cytotoxicity and promoted effector cytokine production in a glucose- and glutamine-dependent manner.

Skeletal muscle antagonizes antiviral CD8 T cell exhaustion.

CD8 T cells become functionally impaired or "exhausted" in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)-15 production during LCMV clone 13 chronic infection.

Dysregulation of very-long-chain fatty acid metabolism causes membrane saturation and induction of the unfolded protein response.

The unfolded protein response (UPR) senses defects in the endoplasmic reticulum (ER) and orchestrates a complex program of adaptive cellular remodeling. Increasing evidence suggests an important relationship between lipid homeostasis and the UPR. Defects in the ER membrane induce the UPR, and the UPR in turn controls the expression of some lipid metabolic genes.

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8 T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8 T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses.

Early TCR Signaling Sweetens Effector Function through PDHK1.

T cells rapidly engage glycolysis upon activation. The signaling pathways through which T cell receptor (TCR) activation initiates glycolysis have been a mystery. A long-awaited answer has been provided by Menk et al.

Phospholipase Lpl1 links lipid droplet function with quality control protein degradation.

Protein misfolding is toxic to cells and is believed to underlie many human diseases, including many neurodegenerative diseases. Accordingly, cells have developed stress responses to deal with misfolded proteins. The transcription factor Rpn4 mediates one such response and is best known for regulating the abundance of the proteasome, the complex multisubunit protease that destroys proteins.