Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-gamma-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-gamma expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-gamma production, but also the protective function of iNKT cells in arthritis

Unique Interplay between Sugar and Lipid in Determining the Antigenic Potency of Bacterial Antigens for NKT Cells

Structural and biophysical studies reveal the induced-fit mechanism underlying the stringent specificity of invariant natural killer T cells for unique glycolipid antigens from the pathogen Streptococcus pneumoniae

Resource depletion in Aedes aegypti mosquitoes infected by the microsporidia Vavraia culicis

International audienc

The T cell antigen receptor expressed by Vα14i NKT cells has a unique mode of glycosphingolipid antigen recognition

Natural killer (NK) T cells with an invariant Vα14 rearrangement (Vα14i) are the largest population of lipid antigen-specific T lymphocytes identified in animals. They react to the glycolipid α-galactosyl ceramide (α-GalCer) presented by CD1d, and they may have important regulatory functions. It was previously shown that the Vα14i T cell antigen receptor (TCR) has a high affinity for the α-GalCer/CD1d complex, driven by a long half-life (t(1/2)). Although this result could have reflected the unique attributes of α-GalCer, using several related glycolipid compounds, we show here that the threshold for full activation of Vα14i NKT cells by these glycosphingolipids requires a relatively high-affinity TCR interaction with a long t(1/2). Furthermore, our data are consistent with the view that the mechanism of recognition of these compounds presented by CD1d to the Vα14i NKT cell TCR is likely to fit a lock-and-key model. Overall, these findings emphasize the distinct properties of glycosphingolipid antigen recognition by Vα14i NKT cells

A longitudinal molecular study of the ecology of malaria infections in free-ranging mandrills

International audienceUnravelling the determinants of host variation in susceptibility and exposure to parasite infections, infection dynamics and the consequences of parasitism on host health is of paramount interest to understand the evolution of complex host-parasite interactions. In this study, we evaluated the determinants, temporal changes and physiological correlates of Plasmodium infections in a large natural population of mandrills (Mandrillus sphinx). Over six consecutive years, we obtained detailed parasitological and physiological data from 100 male and female mandrills of all ages. The probability of infection by Plasmodium gonderi and P. mandrilli was elevated (ca. 40%) but most infections were chronical and dynamic, with several cases of parasite switching and clearance. Positive co-infections also occurred between both parasites. Individual age and sex influenced the probability of infections with some differences between parasites: while P. mandrilli appeared to infect its hosts rather randomly, P. gonderi particularly infected middle-aged mandrills. Males were also more susceptible to P. gonderi than females and were more likely to be infected by this parasite at the beginning of an infection by the simian immunodeficiency virus. P. gonderi, and to a lesser extent P. mandrilli, influenced mandrills' physiology: skin temperatures and neutrophil/lymphocyte ratio were both impacted, generally depending on individual age and sex. These results highlight the ecological complexity of Plasmodium infections in nonhuman primates and the efforts that need to be done to decipher the epidemiology of such parasites

Safety of deferring the reimplantation of pacing systems after their removal for infectious complications in selected patients: A 1-year follow-up study

Introduction: Recent expert consensus guidelines mention that one of the principles for infected device replacement following removal is to "reevaluate carefully if there is a continued need for a new cardiac device replacement." This is a Class I recommendation, which nevertheless suffers from a very low level of evidence (level of evidence C), since no study has revisited the systematic practice of reimplanting the same device based on a meticulous clinical reassessment. In the present paper, we examined the safety of withholding the implantation of pacing systems in selected patients. Methods and Results: Between January 2005 and December 2007, 188 consecutive patients underwent extractions of infected pacing systems at 2 medical centers. "Low-risk" patients were identified by (1) a spontaneous heart rate >45 bpm, (2) no symptomatic asystole during monitoring, (3) QRS duration <120 ms when history of AV block was noted, (4) no high-degree AV block during continuous monitoring. They remained device-free, unless an adverse clinical event occurred mandating the reimplantation. The primary study endpoint was rate of sudden death and syncope after a 12-month follow-up. Among the 74 (39.4%) "low-risk" patients, a single patient suffered a bradycardia-related syncopal event corresponding to a 1.3% (95% CI, 0.0-3.9) rate of primary endpoint. Pacing systems were also reimplanted in 24 patients (32.4%) for syncope (n = 1), nonsevere bradycardia-reated symptoms (n = 17), cardiac resynchronization (n = 2), and for reassurance in 4 asymptomatic patients. Conclusion: After removal of infected pacing systems, these preliminary data demonstrated that a strategy of nonsystematic device reimplantation associated with close surveillance was safe in "low-risk" patients, allowing the administration of antimicrobials in a device-free state. © 2009 Wiley Periodicals, Inc