Interactions of the inhibitory receptor programmed death-1 (PD-1) with its ligands, programmed death ligand (PD-L)1 and PD-L2, regulate T-cell activation and tolerance. In this study, we investigated the role of PD-L1 and PD-L2 in regulating invariant natural killer T (iNKT)-cellmediated airway hyperreactivity (AHR) in a murine model of asthma. We found that the severity of AHR and airway inflammation is significantly greater in PD-L2 −/− mice compared with wild-type mice after either ovalbumin (OVA) sensitization and challenge or administration of α-galactosylceramide (α-GalCer). iNKT cells from PD-L2 −/− mice produced significantly more interleukin (IL)-4 than iNKT cells from control mice. Moreover, blockade of PD-L2 interactions of wild-type iNKT cells in vitro with monoclonal antibodies (mAbs) resulted in significantly enhanced levels of IL-4 production. In contrast, PD-L1 −/− mice showed significantly reduced AHR and enhanced production of interferon-γ (IFN-γ) by iNKT cells. iNKT-deficient Jα18 −/− mice reconstituted with iNKT cells from PD-L2 −/− mice developed high levels of AHR, whereas mice reconstituted with iNKT cells from PD-L1 −/− mice developed lower levels of AHR compared with control. As PD-L2 is not expressed on iNKT cells but rather is expressed on lung dendritic cells (DCs), in which its expression is upregulated by allergen challenge or IL-4, these findings suggest an important role of PD-L2 on lung DCs in modulating asthma pathogenesis. These studies also indicate that PD-L1 and PD-L2 have important but opposing roles in the regulation of AHR and iNKT-cell-mediated activation.

To cite this article: Singh AK, Stock P, Akbari O. Role of PD‐L1 and PD‐L2 in allergic diseases and asthma. Allergy 2011; 66: 155–162. Abstract Asthma is the result of chronic airway inflammation associated predominantly with CD4+ cells, eosinophils, mast cells, and basophils. Several T‐cells subsets, including NKT cells, play a critical role in orchestrating the inflammation in the airways predominantly, by secreting interleukin‐4 and interleukin‐13. Recently, programmed death‐1 (PD‐1) with its ligands, programmed death ligand B7H1 (PD‐L1) and B7DC (PD‐L2), was shown to regulate T‐cell activation and tolerance. PD‐1 has been characterized as a negative regulator of conventional CD4+T cells. In addition, the relative roles of PD‐L1 and PD‐L2 in regulating the activation and function of T cells have recently been characterized. Recent studies have demonstrated that PD‐L1 and PD‐L2 have important but opposing roles in modulating and polarizing T‐cell functions in airway hyperreactivity. Whereas the severity of asthma is greatly enhanced in absence of PD‐L2, PD‐L1 deficiency resulted in reduced airway hyperresponsiveness and only minimal inflammation. This observation is partially because of the polarization of NKT cells in PD‐L1‐ and PD‐L2‐deficient mice. This review will discuss the recent literature regarding the role of PD‐L1 and PD‐L2 in allergic disease and asthma. Current understanding of the role of PD ligands in allergic asthma gives impetus to the development of novel therapeutic approaches.

In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky’s criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.

Data parallel architectures, such as General Purpose Graphics Units (GPGPUs) have seen a tremendous rise in their application for High End Computing. However, data movement in and out of GPGPUs remain the biggest hurdle to overall performance and programmer productivity. Applications executing on a cluster with GPUs have to manage data movement using CUDA in addition to MPI, the de-facto parallel programming standard. Currently, data movement with CUDA and MPI libraries is not integrated and it is not as efficient as possible. In addition, MPI-2 one sided communication does not work for windows in GPU memory, as there is no way to remotely get or put data from GPU memory in a one-sided manner.In this paper, we propose a novel MPI design that integrates CUDA data movement transparently with MPI. The programmer is presented with one MPI interface that can communicate to and from GPUs. Data movement from GPU and network can now be overlapped. The proposed design is incorporated into the MVAPICH2 library. To the best of our knowledge, this is the first work of its kind to enable advanced MPI features and optimized pipelining in a widely used MPI library. We observe up to 45% improvement in one-way latency. In addition, we show that collective communication performance can be improved significantly: 32%, 37% and 30% improvement for Scatter, Gather and Allotall collective operations, respectively. Further, we enable MPI-2 one sided communication with GPUs. We observe up to 45% improvement for Put and Get operations.

The prevalence of allergic diseases has increased rapidly in recent years. It is well established that the deleterious allergic response is initiated by T-cell recognition of major histocompatibility class II-peptide complexes at the surface of antigen-presenting cells. While this first signal gives antigen specificity to the adaptive immune response, a second nonspecific costimulatory signal is required by T cells to become fully activated. This signal is provided by interactions between antigen-presenting cells and T cells through molecules borne at the surfaces of the two cell types. Depending on the type of molecules involved, this secondary signal can promote the development of an inflammatory allergic reaction or may favor immune regulation. Several molecules of the B7 family (CD80, CD86, PD-1, ICOS, CTLA-4) and tumor necrosis factor receptor family (OX40, CD30, 4-1BB, Fas, CD27, CD40) play an important role in delivering costimulatory signals in early and late phases of allergic response. Therefore, costimulatory molecules involved in promotion or prevention of allergic immune responses are potential targets for the development of novel therapeutic approaches. This review aims to recapitulate our current understanding of the relationship between allergic diseases and costimulatory molecules.