Type I mucopolysaccharidosis (MPS I) IntroductionType I mucopolysaccharidosis (MPS I) is one of the most frequent lysosomal storage disorders (LSDs) and is due to the inherited deficiency of ␣-L-iduronidase (IDUA) activity, which results in the accumulation of its unprocessed substrates (glycosaminoglycans; GAGs) in many organs. 1 The disorder is systemic and clinically heterogeneous. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation. The clinical spectrum ranges from the severe Hurler syndrome (MPS I-H) to the attenuated Scheie syndrome. Mental retardation is distinctive only of MPS I-H, which is fatal in childhood if untreated, thus representing the variant with the most urgent need for new therapies. Enzyme replacement therapy (ie, parenteral administration of exogenous enzyme that can be internalized by tissue cells via the mannosium-6-phosphate receptor) is recommended only for MPS I patients without primary neurologic disease, due to the inability of the enzyme to efficiently cross the blood-brain barrier; moreover, neutralizing antibodies can attenuate its efficacy. 2 When performed at early ages, hematopoietic stem cell (HSC) transplantation (HCT) from healthy donors alleviates most disease manifestations in MPS I-H patients, likely by migration of the transplant-derived leukocytes into organs, where they can clear the storage and secrete the functional enzyme for correction of the metabolic defect in resident cells. 3 However, despite recent improvements in the outcome of HCT, the morbidity and mortality associated with the procedure are still not negligible, mostly due to rejection and graft-versus-host disease. Moreover, the amount of enzyme that transplantation can provide to the organism can be limiting, especially since donors are often heterozygous siblings. Indeed, a relationship between circulating enzyme levels after transplant and urinary GAGs has been shown 4 : the low enzyme levels achieved with heterozygote donor transplant lead to less adequate reduction in GAG levels. Likely due to partial metabolic correction at disease sites, the impact of HCT on central nervous system (CNS) and skeletal disease, despite being substantial in ameliorating patients' phenotype, could still benefit from further improvement. 5 The benefits of different gene therapy approaches were established in MPS I animal models. Intravenous delivery of viral vectors, which can establish a tissue source for systemic enzyme distribution, was effective in controlling disease manifestations in The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From MPS I animal models upon neonatal treatment. [6][7][8][9] However, residu...

IntroductionIn addition to their role in providing antitumor and antiviral immunity, 1 natural killer (NK) cells are also able to regulate the T-cell arm of the adaptive immune response by secreting different cytokines and chemokines. 2 Moreover, several studies have provided evidence of cognate cell-cell interactions between NK cells and various leukocyte types, including dendritic cells (DCs) and B and T lymphocytes. [3][4][5] Although NK cells have been thought to mainly promote adaptive immune responses, recent in vivo studies suggest that they can also restrain T cell-mediated immune responses. Therefore, the depletion of NK cells results in enhanced T-cell proliferation and effector functions during murine cytomegalovirus infection 6 and in an antitumor response against lymphoma cells. 7 Conversely, several studies have indicated that the depletion of NK cells is associated with increased severity of autoimmune diseases. In fact, NK cell-depleted mice develop a more severe form of experimental autoimmune encephalomyelitis, 8 and NK-cell-mediated downregulation of autoreactive cytotoxic T lymphocytes has been shown to have a protective role in type 1 diabetes. 9 These findings suggest that NK cells may be crucial for terminating T cell-mediated responses and for preventing inappropriate T-cell activation and effector functions leading to the development of autoimmune diseases.NK cell-mediated attenuation of T-cell responses can involve several mechanisms, including the production of inhibitory cytokines (eg, TGF-␤ and IL-10) 10,11 and killing of DCs and/or activated T cells. 4,12,13 In regard to the NK cell-mediated killing of T cells, IL-2-activated mouse and human NK cells recognize and lyse T-cell blasts in a perforin-dependent manner through the activating receptor NKG2D. 4,12 Interestingly, the results of our previous study indicated that Ag stimulation of human T cells was sufficient to induce the surface expression of the NKG2D ligands (NKG2DLs) MHC class I-related chain A (MICA), MICB, and UL16-binding proteins 1-3 (ULBP1-3). 4,14 To date, little is known about the existence of additional receptor-ligand interactions that might contribute to the NK cell-mediated recognition of T lymphocytes.DNAX accessory molecule-1 (DNAM-1) is an activating receptor belonging to the Ig superfamily that is constitutively expressed by most NK cells, T cells, macrophages, and DCs. 15,16 DNAM-1 interacts with lymphocyte function-associated antigen 1 (LFA-1), and this association is required for its functional activity on both NK and cytotoxic T cells. 17 Ligands for DNAM-1 (DNAM1Ls) include Nectin-2 and poliovirus receptor (PVR), which belong to the Nectin/Nectin-like family of adhesion molecules. 18 DNAM1Ls are often expressed by tumor cells and can activate or enhance tumor cell lysis in vitro. 15,18 Recent studies have reported that they can also be expressed by monocytes, DCs, and phytohemagglutinin (PHA)-stimulated CD4 ϩ T lymphocytes. 19,20 Little information is available about the molecular mechanisms regulating...

Immunomodulatory drugs (IMiDs) have potent anti-tumor activities in multiple myeloma (MM) and are able to enhance the cytotoxic function of natural killer (NK) cells, important effectors of the immune response against MM. Here, we show that these drugs can enhance the expression of the NKG2D and DNAM-1 activating receptor ligands MICA and PVR/CD155 in human MM cell lines and primary malignant plasma cells. Depletion of cereblon (CRBN) by shRNA interference strongly impaired upregulation of these ligands and, more interestingly, IMiDs/CRBN-mediated downregulation of the transcription factors Ikaros (IKZF1), Aiolos (IKZF3) and IRF4 was critical for these regulatory mechanisms. Indeed, shRNA knockdown of IKZF1 or IKZF3 expression was both necessary and sufficient for the upregulation of MICA and PVR/CD155 expression, suggesting that these transcription factors can repress these genes; accordingly, the direct interaction and the negative role of IKZF1 and IKZF3 proteins on MICA and PVR/CD155 promoters were demonstrated. Finally, MICA expression was enhanced in IRF4-silenced cells, indicating a specific suppressive role of this transcription factor on MICA gene expression in MM cells.Taken together, these findings describe novel molecular pathways involved in the regulation of MICA and PVR/CD155 gene expression and identify the transcription factors IKZF-1/IKZF-3 and IRF4 as repressors of these genes in MM cells.