Distinct roles of prostaglandin H synthases 1 and 2 in T-cell development

Prostaglandin G and H synthases, or cyclooxygenases (COXs), catalyze the formation of prostaglandins (PGs). Whereas COX-1 is diffusely expressed in lymphoid cells in embryonic day 15.5 thymus, COX-2 expression is sparse, apparently limited to stromal cells. By contrast, COX-2 is predominant in a subset of medullary stromal cells in three- to five-week-old mice. The isozymes also differ in their contributions to lymphocyte development. Thus, experiments with selective COX-1 inhibitors in thymic lobes from normal and recombinase-activating gene-1 knockout mice support a role for this isoform in the transition from CD4(-)CD8(-) double-negative (DN) to CD4(+)CD8(+) double-positive (DP). Concordant data were obtained in COX-1 knockouts. Pharmacological inhibition and genetic deletion of COX-2, by contrast, support its role during early thymocyte proliferation and differentiation and, later, during maturation of the CD4 helper T-cell lineage. PGE2, but not other PGs, can rescue the effects of inhibition of either isoform, although it acts through distinct EP receptor subtypes. COX-dependent PG generation may represent a mechanism of thymic stromal support for T-cell development.     

Fasten the seat belt: Increasing safety of CAR T-cell therapy

After the recent success and approvals of chimeric antigen receptor (CAR) T cells in haematological malignancies, its efficacy is currently evaluated in a broad spectrum of tumor entities including melanoma. However, severe and potentially life-threatening side effects like cytokine release syndrome, neurologic toxicities, and the competing risk of morbidity and mortality from the treatment itself are still a major limiting factor in the current CAR T-cell landscape. In addition, especially in solid tumors, the lack of ideal target antigens to avoid on-target/off-tumor toxicities also restricts its use. While various groups are working on strategies to boost CAR T-cell efficacy, mechanisms to increase engineered T-cell safety should not move out of focus. Thus, the aim of this article is to summarize and to discuss current and potential future strategies and mechanisms to increase CAR T-cell safety in order to enable the wide use of this promising approach in melanoma and other tumor entities.     

Motor skill acquisition during a balance task as a process of optimization of motor primitives

It has been argued that the central nervous system relies on combining simple movement elements (i.e. motor primitives) to generate complex motor outputs. However, how movement elements are generated and combined during the acquisition of new motor skills is still a source of debate. Herein, we present results providing new insights into the role of movement elements in the acquisition of motor skills that we obtained by analysing kinematic data collected while healthy subjects learned a new motor task. The task consisted of playing an interactive game using a platform with embedded sensors whose aggregate output was used to control a virtual object in the game. Subjects learned the task over multiple blocks. The analysis of the kinematic data was carried out using a recently developed technique referred to as “movement element decomposition.” The technique entails the decomposition of complex multi‐dimensional movements in one‐dimensional elements marked by a bell‐shaped velocity profile. We computed the number of movement elements during each block and measured how closely they matched a theoretical velocity profile derived by minimizing a cost function accounting for the smoothness of movement and the cost of time. The results showed that, in the early stage of motor skill acquisition, two mechanisms underlie the improvement in motor performance: 1) a decrease in the number of movement elements composing the motor output and 2) a gradual change in the movement elements that resulted in a shape matching the velocity profile derived by using the above‐mentioned theoretical model.     

Macrophage-Derived Vascular Endothelial Growth Factor-A Is Integral to Neuromuscular Junction Reinnervation after Nerve Injury

Functional recovery in the end target muscle is a determinant of outcome after peripheral nerve injury. The neuromuscular junction (NMJ) provides the interface between nerve and muscle and includes non-myelinating terminal Schwann cells (tSCs). After nerve injury, tSCs extend cytoplasmic processes between NMJs to guide axon growth and NMJ reinnervation. The mechanisms related to NMJ reinnervation are not known. We used multiple mouse models to investigate the mechanisms of NMJ reinnervation in both sexes, specifically whether macrophage-derived vascular endothelial growth factor-A (Vegf-A) is crucial to establishing NMJ reinnervation at the end target muscle. Both macrophage number and Vegf-A expression increased in end target muscles after nerve injury and repair. In mice with impaired recruitment of macrophages and monocytes (Ccr2−/− mice), the absence of CD68+ cells (macrophages) in the muscle resulted in diminished muscle function. Using a Vegf-receptor 2 (VegfR2) inhibitor (cabozantinib; CBZ) via oral gavage in wild-type (WT) mice resulted in reduced tSC cytoplasmic process extension and decreased NMJ reinnervation compared with saline controls. Mice with Vegf-A conditionally knocked out in macrophages (Vegf-A^fl/fl; LysM^Cre mice) demonstrated a more prolonged detrimental effect on NMJ reinnervation and worse functional muscle recovery. Together, these results show that contributions of the immune system are integral for NMJ reinnervation and functional muscle recovery after nerve injury.SIGNIFICANCE STATEMENT This work demonstrates beneficial contributions of a macrophage-mediated response for neuromuscular junction (NMJ) reinnervation following nerve injury and repair. Macrophage recruitment occurred at the NMJ, distant from the nerve injury site, to support functional recovery at the muscle. We have shown hindered terminal Schwann cell (tSC) injury response and NMJ recovery with inhibition of: (1) macrophage recruitment after injury; (2) vascular endothelial growth factor receptor 2 (VegfR2) signaling; and (3) Vegf secretion from macrophages. We conclude that macrophage-derived Vegf is a key component of NMJ recovery after injury. Determining the mechanisms active at the end target muscle after motor nerve injury reveals new therapeutic targets that may translate to improve motor recovery following nerve injury.