IntroductionHuman cytomegalovirus (HCMV) infection is highly prevalent in healthy persons and the virus remains in a lifelong latent state, undergoing occasional reactivation and causing an important morbidity in immunocompromised patients. 1 An effective defense against CMV infection requires the participation of both T and NK cells. 2 To escape T cell-mediated recognition, CMV interferes with the expression of major histocompatibility complex molecules and antigen presentation. 3 The loss of human leukocyte antigen (HLA) class I molecules in infected cells impairs the engagement of inhibitory receptors, thus promoting the activation of NK-cell effector functions. Reciprocally, the virus has developed different strategies to escape NK-cell surveillance, preventing the expression of ligands for some activating receptors (ie, NKG2D, DNAM-1) 4-9 or selectively maintaining inhibitory receptors for HLA class I molecules engaged. The UL18 glycoprotein binds with high affinity to the LILRB1 inhibitory receptor expressed in different leukocytes 10 ; yet, formal experimental evidence for its function in immune evasion remains elusive. 11 In the same line, a leader signal peptide of the UL40 HCMV protein was shown to stabilize the surface expression of HLA-E, thus repressing NK-cell activation by engagement of the inhibitory CD94/NKG2A receptor. 12,13 On the other hand, the NK-cell subset bearing the CD94/NKG2C triggering molecule tends to expand in peripheral blood from HCMV ϩ persons 14 and on in vitro coculture of peripheral blood mononuclear cells (PBMCs) with HCMV-infected fibroblasts. 15 A CD94/NKG2C ϩ NK lymphocytosis was detected in a patient with a selective T-cell deficiency, coinciding with an acute HCMV infection and associated with a reduction of viremia. 16 Altogether, these results suggest that the CD94/NKG2C ϩ NK-cell subset may play an active role in the response to HCMV.Information on the nature of NK-cell receptor (NKR)-ligand interactions involved in the response against HCMV-infected cells is scarce, and most studies have been performed in infected fibroblasts, not fully representative of the different cell types susceptible to in vivo infection. Cells of the myeloid lineage are considered reservoirs for HCMV latency, and differentiation of myeloid progenitors to dendritic cells (DCs) may reactivate the virus. 17 Furthermore, monocyte-derived DCs (moDCs) appear susceptible to in vitro HCMV infection by endothelial cell (EC)-adapted viral strains. 18 Infection of moDCs has been reported to impair their maturation, inhibiting surface expression of major histocompatibility complex class I and II, costimulatory molecules, and chemokine receptors (ie, CCR1 and CCR5), thus interfering with the development of virus-specific T-cell responses. [19][20][21] Beyond their key role in antigen presentation, DCs may establish a cross-talk with NK cells that reciprocally regulates their Submitted August 9, 2010; accepted October 13, 2010. Prepublished online as Blood First Edition paper, October 28, 2010; DOI 10.118...

Human cytomegalovirus (HCMV) infection promotes a persistent expansion of a function-Keywords: CD94/NKG2C r Cytomegalovirus r Human r NK cells r NKG2C genotype Additional supporting information may be found in the online version of this article at the publisher's web-site

Cell-fusion-mediated somatic-cell reprogramming can be induced in culture; however, whether this process occurs in mammalian tissues remains enigmatic. Here, we show that upon activation of Wnt/β-catenin signaling, mouse retinal neurons can be transiently reprogrammed in vivo back to a precursor stage. This occurs after their spontaneous fusion with transplanted hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that retinal damage is essential for cell-hybrid formation in vivo. Newly formed hybrids can proliferate, commit to differentiation toward a neuroectodermal lineage, and finally develop into terminally differentiated neurons. This results in partial regeneration of the damaged retinal tissue, with functional rescue. Following retinal damage and induction of Wnt/β-catenin signaling, cell-fusion-mediated reprogramming also occurs after endogenous recruitment of bone-marrow-derived cells in the eyes. Our data demonstrate that in vivo reprogramming of terminally differentiated retinal neurons after their fusion with HSPCs is a potential mechanism for tissue regeneration.

Human cytomegalovirus (hCMV) infection is usually asymptomatic but may cause disease in immunocompromised hosts. It has been reported that hCMV infection may shape the NK cell receptor (NKR) repertoire in adult individuals, promoting a variable expansion of the CD94/NKG2C1 NK cell subset. We explored the possible relationship between this viral infection and the expression pattern of different NKR including CD94/NKG2C, CD94/ NKG2A, immunoglobulin-like transcript 2 (ILT2, CD85j), KIR2DL1/2DS1, KIR3DL1, and CD161 in peripheral blood lymphocytes from healthy children, seropositive (n 5 21) and seronegative (n 5 20) for hCMV. Consistent with previous observations in adults, a positive serology for hCMV was associated with increased numbers of NKG2C 1 NK and T cells as well as with ILT2 1 T lymphocytes. Moreover, the proportions of CD161 1 andÀ NK cells also tended to be increased in hCMV 1 individuals. Excretion of the virus was associated with higher proportions of NKG2C 1 NK cells. Altogether, these data reveal that hCMV may have a profound influence on the NKR repertoire in early childhood.

Vision impairments and blindness caused by retinitis pigmentosa result from severe neurodegeneration that leads to a loss of photoreceptors, the specialized light-sensitive neurons that enable vision. Although the mammalian nervous system is unable to replace neurons lost due to degeneration, therapeutic approaches to reprogram resident glial cells to replace retinal neurons have been proposed. Here, we demonstrate that retinal Müller glia can be reprogrammed in vivo into retinal precursors that then differentiate into photoreceptors. We transplanted hematopoietic stem and progenitor cells (HSPCs) into retinas affected by photoreceptor degeneration and observed spontaneous cell fusion events between Müller glia and the transplanted cells. Activation of Wnt signaling in the transplanted HSPCs enhanced survival and proliferation of Müller-HSPC hybrids as well as their reprogramming into intermediate photoreceptor precursors. This suggests that Wnt signaling drives the reprogrammed cells toward a photoreceptor progenitor fate. Finally, Müller-HSPC hybrids differentiated into photoreceptors. Transplantation of HSPCs with activated Wnt functionally rescued the retinal degeneration phenotype in rd10 mice, a model for inherited retinitis pigmentosa. Together, these results suggest that photoreceptors can be generated by reprogramming Müller glia and that this approach may have potential as a strategy for reversing retinal degeneration.