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

Atypical natural killer T-cell receptor recognition of CD1d-lipid antigens

Crucial to Natural Killer T (NKT) cell function is the interaction between their T-cell receptor (TCR) and CD1d-antigen complex. However, the diversity of the NKT cell repertoire and the ensuing interactions with CD1d-antigen remain unclear. We describe an atypical population of CD1d-α-galactosylceramide (α-GalCer)-reactive human NKT cells that differ markedly from the prototypical TRAV10-TRAJ18-TRBV25-1(+) type I NKT cell repertoire. These cells express a range of TCR α- and β-chains that show differential recognition of glycolipid antigens. Two atypical NKT TCRs (TRAV21-TRAJ8-TRBV7-8 and TRAV12-3-TRAJ27-TRBV6-5) bind orthogonally over the A'-pocket of CD1d, adopting distinct docking modes that contrast with the docking mode of all type I NKT TCR-CD1d-antigen complexes. Moreover, the interactions with α-GalCer differ between the type I and these atypical NKT TCRs. Accordingly, diverse NKT TCR repertoire usage manifests in varied docking strategies and specificities towards CD1d-α-GalCer and related antigens, thus providing far greater scope for diverse glycolipid antigen recognition

Awareness and use of intertrochanteric osteotomies in current clinical practice. An international survey

Current literature shows that intertrochanteric osteotomies can produce excellent results in selected hip disorders in specific groups of patients. However, it appears that this surgical option is considered an historical one that has no role to play in modern practice. In order to examine current awareness of and views on intertrochanteric osteotomies among international hip surgeons, an online survey was carried out. The survey consisted of a set of questions regarding current clinical practice and awareness of osteotomies. The second part of the survey consisted of five clinical cases and sought to elicit views on preoperative radiological investigations and preferred (surgical) treatments. The results of our survey showed that most of these experts believe that intertrochanteric osteotomies should still be performed in selected cases. Only 56% perform intertrochanteric osteotomies themselves and of those, only 11% perform more than five per year. The responses to the cases show that about 30–40% recommend intertrochanteric osteotomies in young symptomatic patients. This survey shows that the role of intertrochanteric osteotomies is declining in clinical practice

Modulation of NKT Cell Development by B7-CD28 Interaction: An Expanding Horizon for Costimulation

It has been demonstrated that the development of NKT cells requires CD1d. The contribution of costimulatory molecules in this process has not been studied. Here we show that in mice with targeted mutations of B7-1/2 and CD28, the TCRβ+α-Galcer/CD1d + (iVα14 NKT) subset is significantly reduced in the thymus, spleen and liver. This is mainly due to decreased cell proliferation; although increased cell death in the thymi of CD28-deficient mice was also observed. Moreover, in the B7-1/2- and CD28-deficient mice, we found a decreased percentage of the CD4−NK1.1+ subset and a correspondingly increased portion of the CD4+NK1.1− subset. In addition, the mice with a targeted mutation of either B7 or CD28 had a reduced susceptibility to Con A induced hepatitis, which is known to be mediated by NKT cells. Our results demonstrate that the development, maturation and function of NKT cell are modulated by the costimulatory pathway and thus expand the horizon of costimulation into NKT, which is widely viewed as a bridge between innate and adaptive immunity. As such, costimulation may modulate all major branches of cell-mediated immunity, including T cells, NK cells and NKT cells

EMS Systems: Foundations for the Future

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73462/1/j.1553-2712.1999.tb00094.x.pd

Recognition of vitamin B metabolites by mucosal-associated invariant T cells

The mucosal-associated invariant T-cell antigen receptor (MAIT TCR) recognizes MR1 presenting vitamin B metabolites. Here we describe the structures of a human MAIT TCR in complex with human MR1 presenting a non-stimulatory ligand derived from folic acid and an agonist ligand derived from a riboflavin metabolite. For both vitamin B antigens, the MAIT TCR docks in a conserved manner above MR1, thus acting as an innate-like pattern recognition receptor. The invariant MAIT TCR a-chain usage is attributable to MR1-mediated interactions that prise open the MR1 cleft to allow contact with the vitamin B metabolite. Although the non-stimulatory antigen does not contact the MAIT TCR, the stimulatory antigen does. This results in a higher affinity of the MAIT TCR for a stimulatory antigen in comparison with a non-stimulatory antigen. We formally demonstrate a structural basis for MAIT TCR recognition of vitamin B metabolites, while illuminating how TCRs recognize microbial metabolic signatures

An Electrode Array for Limiting Blood Loss During Liver Resection: Optimization via Mathematical Modeling

Liver resection is the current standard treatment for patients with both primary and metastatic liver cancer. The principal causes of morbidity and mortality after liver resection are related to blood loss (typically between 0.5 and 1 L), especially in cases where transfusion is required. Blood transfusions have been correlated with decreased long-term survival, increased risk of perioperative mortality and complications. The goal of this study was to evaluate different designs of a radiofrequency (RF) electrode array for use during liver resection. The purpose of this electrode array is to coagulate a slice of tissue including large vessels before resecting along that plane, thereby significantly reducing blood loss. Finite Element Method models were created to evaluate monopolar and bipolar power application, needle and blade shaped electrodes, as well as different electrode distances. Electric current density, temperature distribution, and coagulation zone sizes were measured. The best performance was achieved with a design of blade shaped electrodes (5 × 0.1 mm cross section) spaced 1.5 cm apart. The electrodes have power applied in bipolar mode to two adjacent electrodes, then switched sequentially in short intervals between electrode pairs to rapidly heat the tissue slice. This device produces a ~1.5 cm wide coagulation zone, with temperatures over 97 ºC throughout the tissue slice within 3 min, and may facilitate coagulation of large vessels