Background: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods: We performed multiparametric cytofluorimetric analysis of PD-1 1 NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results: We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A 2 KIR 1 CD57 1 phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their

IntroductionNatural killer (NK) cells represent a minor population (5%-20%) of peripheral blood lymphocytes that is also present in secondary lymphoid organs, such as spleen, and lymph nodes, as well as in liver, bone marrow, and maternal uterus. [1][2][3] The function of NK cells in humans is regulated by a balance between opposite signals delivered by a set of HLA class I-specific inhibitory receptors and by a number of activating receptors and coreceptors responsible for NK cell triggering. By the combined use of these receptors, NK cells can discriminate between normal HLA class I ϩ cells and cells that have lost the expression of HLA class I molecules as a consequence of tumor transformation or viral infection. [4][5][6][7] Most NK cells in peripheral blood express the CD56 low CD16 ϩ phenotype, whereas the remainders are CD56 high CD16 Ϫ cells. It was proposed that CD56 high NK cells represent a primary source of immunoregulatory cytokines, whereas the CD56 low C16 ϩ subset represents the principal cytotoxic population. 8 During inflammation, viral infection and tumor growth, NK cells are rapidly recruited from the blood into injured tissues. 9-11 NK cell recruitment is governed by integrated signals, which include adhesion molecules and chemotactic factors. CD56 low CD16 ϩ NK cells express both ␤1 and ␤2 integrins, as well as the ligands for E-and P-selectins. In addition to these molecules, CD56 high NK cells also express high levels of L-selectin, a pivotal molecule for the interaction with lymph node high endothelial venules. 12-14 With respect to chemokine receptors, CD56 low CD16 ϩ NK cells express high levels of CXCR1 and CX3CR1. 9,15 By contrast, CD56 high NK cells express CCR7 as well as CCR5 and CXCR3. 8,9,15 It is likely that the different expression profile of adhesion molecules and chemokine receptors between the 2 major blood NK cell subsets is responsible for the preferential migration of CD56 low CD16 ϩ and CD56 high CD16 Ϫ NK cells into inflamed tissues and secondary lymphoid organs, respectively. 16 In fact, the CD56 high CD16 Ϫ NK cell subset although poorly represented in peripheral blood constitutes the only type of NK cells present in secondary lymphoid tissues. 2,3 We have recently identified a novel protein, chemerin, as the natural ligand of the previously orphan receptor ChemR23. 17 ChemR23 exhibits a unique expression profile among leukocyte populations being expressed preferentially by monocyte/macrophages and by immature myeloid and plasmacytoid dendritic cells (DCs). 18 Chemerin, originally isolated from inflamed biologic fluids, such as ovarian cancer ascites and rheumatoid arthritis synovial fluids, is synthesized as a secreted precursor protein.Prochemerin is poorly active but can be rapidly converted into a full ChemR23 agonist by the proteolytic removal of the last 6 amino acids by neutrophil-derived proteases (elastase and cathepsin G), mast cell products (triptase), and proteases of the coagulation cascade. 19,20 Therefore, prochemerin represents a "ready to The online ...

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Background Combined immunodeficiencies (CIDs) denote inborn errors of T-cell immunity with T cells present but quantitatively or functionally deficient. Impaired humoral immunity, either due to a primary B cell defect or secondary to the T-cell defect, is also frequent. Consequently, patients with CID display severe infections and/or autoimmunity. The specific molecular, cellular, and clinical features of many types of CID remain unknown. Methods We performed genetic and cellular immunological studies in five unrelated children who shared a history of early-onset invasive bacterial and viral infections, with lymphopenia and defective T-, B-, and NK-cell responses. Two patients died early in childhood, whereas the other three underwent allogeneic hematopoietic stem cell transplantation with normalization of T cell function and clinical improvement. Results We identified bi-allelic mutations in the Dedicator Of Cytokinesis 2 (DOCK2) gene in these five patients. RAC1 activation was impaired in T cells. Chemokine-induced migration and actin polymerization were defective in T, B, and NK cells. NK-cell degranulation was also affected. The production of interferon (IFN)-α and -λ by peripheral blood mononuclear cells (PBMCs) was diminished following virus infection. Moreover, in DOCK2-deficient fibroblasts, virus replication was increased and there was enhanced virus-induced cell death, which could be normalized by treatment with IFN-α2β or upon expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a Mendelian disorder with pleiotropic defects of hematopoietic and non-hematopoietic immunity. Children with clinical features of CID, especially in the presence of early-onset, invasive infections may have this condition.

Akt is a central player in the signal transduction pathways activated in response to many growth factors, hormones, cytokines, and nutrients and is thought to control a myriad of cellular functions including proliferation and survival, autophagy, metabolism, angiogenesis, motility, and exocytosis. Moreover, dysregulated Akt activity is being implicated in the pathogenesis of a growing number of disorders, including cancer. Evidence accumulated over the past 15 years has highlighted the presence of active Akt in the nucleus, where it acts as a fundamental component of key signaling pathways. For example, nuclear Akt counteracts apoptosis through a block of caspase-activated DNase: deoxyribonuclease and inhibition of chromatin condensation, and is also involved in cell cycle progression control, cell differentiation, mRNA: messenger RNA export, DNA repair, and tumorigenesis. In this review, we shall summarize the most relevant findings about nuclear Akt and its functions.

In this study the phenotype and function of tumor-associated NK cells from peritoneal fluids of a selected cohort of patients with seropapillary ovarian carcinoma were analyzed. In > 50% of these patients, the expression of the activating receptor NKp30 in tumor-associated NK cells was substantially reduced as compared to autologous peripheral blood (PB) NK cells. The impaired expression of this receptor was associated with the presence of one of its cellular ligands (B7-H6), which was detectable as a surface/cytosolic molecule in tumor cells and as a soluble molecule in the peritoneal fluid. NK cells from patients expressing this NKp30low phenotype displayed an impaired interferon-gamma (IFNγ) production and cytolytic function when tested against target cells expressing surface B7-H6. Our data also suggest that in these patients, the defective expression and function of NKp30 may be induced by the chronic engagement of this receptor by soluble B7-H6 or by tumor cells expressing this ligand. The impairment of NK cell functions described herein could represent a novel mechanism by which the tumor microenvironment may contribute to the escape from immune surveillance.

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A homozygous mutation that gave rise to a stop codon in the WIPF1 gene resulted in WASP protein destabilization and in symptoms resembling those of Wiskott-Aldrich syndrome