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

Acetate Promotes T Cell Effector Function during Glucose Restriction.

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer

Long Time to Diagnosis of Medulloblastoma in Children Is Not Associated with Decreased Survival or with Worse Neurological Outcome

International audienceBACKGROUND: The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae. PATIENTS AND METHODS: This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome. RESULTS: The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31-121, range 3-457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup. CONCLUSIONS: We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims

EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism

EBF1 and PAX5 mutations are associated with the development of B progenitor acute lymphoblastic leukemia (B-ALL) in humans. To understand the molecular networks driving leukemia in the Ebf1+/−Pax5+/− (dHet) mouse model for B-ALL, we interrogated the transcriptional profiles and chromatin status of leukemic cells, preleukemic dHet pro-B, and wild-type pro-B cells with the corresponding EBF1 and Pax5 cistromes. In dHet B-ALL cells, many EBF1 and Pax5 target genes encoding pre-BCR signaling components and transcription factors were down-regulated, whereas Myc and genes downstream from IL-7 signaling or associated with the folate pathway were up-regulated. We show that blockade of IL-7 signaling in vivo and methotrexate treatment of leukemic cells in vitro attenuate the expansion of leukemic cells. Single-cell RNA-sequencing revealed heterogeneity of leukemic cells and identified a subset of wild-type pro-B cells with reduced Ebf1 and enhanced Myc expression that show hallmarks of dHet B-ALL cells. Thus, EBF1 and Pax5 may safeguard early stage B cells from transformation to B-ALL by limiting IL-7 signaling, folate metabolism and Myc expression

Age- and sex-adjusted all-cause and cardiovascular-related¹ one-year mortality (from incident diagnosis) by cardiovascular disease, per 100 persons, in the Métis and general Ontario population, April 1 2006 to March 31 2012.

<p>CI: Confidence Interval</p><p>¹ ICD 9/10 diagnostic codes to define cardiovascular-related mortality were obtained from: Statistics Canada. Comparability of ICD-10 and ICD-9 for Mortality Statistics in Canada. Ottawa ON, 2005. ICD-9 codes: 390–448. ICD-10 codes: I00-I78.</p><p>Age- and sex-adjusted all-cause and cardiovascular-related^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0121779#t004fn002" target="_blank">1</a>} one-year mortality (from incident diagnosis) by cardiovascular disease, per 100 persons, in the Métis and general Ontario population, April 1 2006 to March 31 2012.</p

Cardiovascular disease types and corresponding definitions in province-wide health administrative databases.

<p>ICD: International Classification of Diseases, version 9 or 10; OHIP: Ontario Health Insurance Plan; DAD: Discharge Abstract Database; NACRS: National Ambulatory Care Reporting System; PPV: Positive predictive value; MRD: most responsible diagnosis; N/A: Not available</p><p>¹ A similar validated algorithm published (using [OHIP + DAD claim] in place of [NACRS + 2^nd NACRS (2 claims in any study year)]: Schultz SE, Rothwell DM, Chen Z, Tu K. Identifying cases of congestive heart failure from administrative data: a validation study using primary care patient records. Chronic Dis Inj Can 2013; 33(3): 160–6.</p><p>² Single NACRS I480 main diagnosis: Atzema CL, Austin PC, Miller E, Chong AC, Yun L, Dorian P. A population-based description of atrial fibrillation in the emergency department, 2002–2010. Ann Emerg Med 2013;62(6):570–7</p><p>³ Validated algorithm published at: Tu K, Campbell NR, Chen Z, Cauch-Dudek K, McAlister FA. Accuracy of administrative databases in identifying patients with hypertension. Open Med 2007; 1(1): 18–26.</p><p>Cardiovascular disease types and corresponding definitions in province-wide health administrative databases.</p

Demographic characteristics of the Métis and the general Ontario population as of April 1, 2006.

<p>IQR: Interquartile Range</p><p>¹Income quintile was determined from postal codes obtained from the Registered Persons Database and neighbourhood-level median household income from Statistics Canada census data. Quintiles range from poorest (Q1) to wealthiest (Q5).</p><p>Demographic characteristics of the Métis and the general Ontario population as of April 1, 2006.</p

Age- and sex-adjusted rate ratios of one-year disease-specific hospitalizations (from incident diagnosis) by cardiovascular disease, in the Métis and general Ontario population, April 1 2006 to March 31 2012.

<p>CI: Confidence Interval</p><p>* p <0.05</p><p>Age- and sex-adjusted rate ratios of one-year disease-specific hospitalizations (from incident diagnosis) by cardiovascular disease, in the Métis and general Ontario population, April 1 2006 to March 31 2012.</p

Quality of care measures after incident cardiovascular disease diagnosis in the Métis and the rest of the Ontario population, April 1 2006 to March 31 2011.

<p>CI: Confidence Interval</p><p>¹ Defined as frequency of beta-blocker use within 3 months after incident diagnosis in persons aged 65+</p><p>² Defined as frequency of outpatient echocardiogram within 6 months of incident diagnosis</p><p>³ Defined as age- and sex-adjusted rate ratio of emergency department visits in the year after incident diagnosis</p><p>* p<0.05</p><p>Quality of care measures after incident cardiovascular disease diagnosis in the Métis and the rest of the Ontario population, April 1 2006 to March 31 2011.</p