Caught in the cROssfire: GSH Controls T Cell Metabolic Reprogramming

T cell activation and proliferation critical for protective immunity depend on appropriate rewiring of cellular metabolism. In this issue of Immunity, Mak et al. (2017) show that the antioxidant gluthathione (GSH) controls reactive oxygen species (ROS)-dependent engagement of metabolic signaling pathways that lead to protective T cell responses

Did changing primary care delivery models change performance? A population based study using health administrative data

<p>Abstract</p> <p>Background</p> <p>Primary care reform in Ontario, Canada started with the introduction of new enrollment models, the two largest of which are Family Health Networks (FHNs), a capitation-based model, and Family Health Groups (FHGs), a blended fee-for-service model. The purpose of this study was to evaluate differences in performance between FHNs and FHGs and to compare performance before and after physicians joined these new primary care groups.</p> <p>Methods</p> <p>This study used Ontario administrative claims data to compare performance measures in FHGs and FHNs. The study population included physicians who belonged to a FHN or FHG for at least two years. Patients were included in the analyses if they enrolled with a physician in the two years after the physician joined a FHN or FHG, and also if they saw the physician in a two year period prior to the physician joining a FHN or FHG. Performance was derived from the administrative data, and included measures of preventive screening for cancer (breast, cervical, colorectal) and chronic disease management (diabetes, heart failure, asthma).</p> <p>Results</p> <p>Performance measures did not vary consistently between models. In some cases, performance approached current benchmarks (Pap smears, mammograms). In other cases it was improving in relation to previous measures (colorectal cancer screening). There were no changes in screening for cervical cancer or breast cancer after joining either a FHN or FHG. Colorectal cancer screening increased in both FHNs and FHGs. After enrolling in either a FHG or a FHN, prescribing performance measures for diabetes care improved. However, annual eye examinations decreased for younger people with diabetes after joining a FHG or FHN. There were no changes in performance measures for heart failure management or asthma care after enrolling in either a FHG or FHN.</p> <p>Conclusions</p> <p>Some improvements in preventive screening and diabetes management which were seen amongst people after they enrolled may be attributed to incentive payments offered to physicians within FHGs and FHNs. However, these primary care delivery models need to be compared with other delivery models and fee for service practices in order to describe more specifically what aspects of model delivery and incentives affect care.</p

Mitochondrial Priming by CD28

T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation—cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses

Dynamic Cardiolipin Synthesis Is Required for CD8⁺ T Cell Immunity

Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity

Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation

How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis

The Importance of methionine metabolism

T helper cells import the amino acid methionine to synthesize new proteins and to provide the methyl groups needed for the methylation of RNA and DNA that drives T cell proliferation and differentiation

Unraveling the Complex Interplay Between T Cell Metabolism and Function

Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies