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The cytolytic T lymphocyte protease granzyme A (GzmA) initiates a caspase-independent cell death pathway. Here we report that the rate-limiting enzyme of DNA base excision repair, apurinic endonuclease-1 (Ape1), which is also known as redox factor-1 (Ref-1), binds to GzmA and is contained in the SET complex, a macromolecular complex of 270-420 kDa that is associated with the endoplasmic reticulum and is targeted by GzmA during cell-mediated death. GzmA cleaves Ape1 after Lys31 and destroys its known oxidative repair functions. In so doing, GzmA may block cellular repair and force apoptosis. In support of this, cells with silenced Ape1 expression are more sensitive, whereas cells overexpressing noncleavable Ape1 are more resistant, to GzmA-mediated death.

Despite the frequency of HIV-specific CD8 T cells, most HIV-infected patients do not control viral replication without antiviral drugs. Although CD8 T cells are important in containing acute HIV and simian immunodeficiency virus (SIV) infection, CD8 T-cell functions are compromised in chronic infection. To investigate whether functional deficits are specific to HIV, the phenotypic and functional properties of HIV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV)–specific CD8 T cells, labeled with HLA A2.1 or B8 tetramers, were compared in 35 HIV-infected and 9 healthy donors. Cytotoxic T lymphocytes express the cytolytic molecules perforin and granzymes, and are thought to be CD45RA+CD27−. Although most HIV- specific cells are antigen experienced and express granzyme A (median, 85%), few express high levels of perforin (median, 10%) or CD45RA (median, 14%) or have down-modulated CD27 (median, 12%). Perforin expression by HIV-specific cells is not significantly different from that of EBV- or CMV-specific cells in the same donors or in healthy donors. EBV- and CMV-specific cells, like HIV-specific cells, are often not cytotoxic when tested directly ex vivo. HIV-specific T-cell expression of other phenotypic markers is similar to that of EBV- and CMV-specific CD8 T cells in healthy donors. However, CMV-specific cells (and, to a lesser extent, EBV-specific cells) in HIV-infected donors are more likely to be CD27−, CD45RA+, and GzmA+. These results suggest that the chance to eradicate an infection by T-cell–mediated lysis may be undermined once an infection becomes chronic. Impaired antiviral cytotoxicity during chronic infection is not specific to HIV but likely represents the immune response to chronic antigenic exposure.

One-dimensional microstructure has been regarded as one of the most desirable configurations for magnetic carbon-based microwave absorbing materials (MAMs). Herein, pea-like Fe/Fe 3 C nanoparticles embedded in nitrogen-doped carbon nanotubes (Fe/Fe 3 C@NCNTs) are successfully prepared through a direct pyrolysis of the mixture of FeCl 3 •6H 2 O and melamine under inert atmosphere. The chemical composition and microstructural feature of these Fe/ Fe 3 C@NCNTs composites are highly dependent on the pyrolysis temperature. As a result, their electromagnetic properties can be also manipulated, where dielectric loss gradually decreases with the increasing pyrolysis temperature and magnetic loss presents a reverse variation trend. When the pyrolysis temperature reaches 600 °C, the as-obtained composite, Fe/Fe 3 C@NCNTs-600 can perform a maximum reflection loss of −46.0 dB at 3.6 GHz with a thickness of 4.97 mm and a qualified bandwidth of 14.8 GHz with the integrated thickness from 1.00 to 5.00 mm. It is very interesting that the microwave absorption performance of this new kind of composites is not so susceptible to the pyrolysis temperature as those common magnetic carbon-based MAMs because there is an effective balance between dielectric loss and magnetic loss, which accounts for a very stable attenuation ability when the pyrolysis temperature range changes from 600 to 700 °C. These favorable characteristics, including low-cost raw materials, easy preparation, and stable performance, may render Fe/Fe 3 C@NCNTs composites as a novel kind of MAMs in the future.

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Coordination between osteoblasts and osteoclasts is required for bone health and homeostasis. Here we show that mice deficient in SMURF2 have severe osteoporosis in vivo. This low bone mass phenotype is accompanied by a pronounced increase in osteoclast numbers, although Smurf2-deficient osteoclasts have no intrinsic alterations in activity. Smurf2-deficient osteoblasts display increased expression of RANKL, the central osteoclastogenic cytokine. Mechanistically, SMURF2 regulates RANKL expression by disrupting the interaction between SMAD3 and vitamin D receptor by altering SMAD3 ubiquitination. Selective deletion of Smurf2 in the osteoblast lineage recapitulates the phenotype of germline Smurf2-deficient mice, indicating that SMURF2 regulates osteoblast-dependent osteoclast activity rather than directly affecting the osteoclast. Our results reveal SMURF2 as an important regulator of the critical communication between osteoblasts and osteoclasts. Furthermore, the bone mass phenotype in Smurf2- and Smurf1-deficient mice is opposite, indicating that SMURF2 has a non-overlapping and, in some respects, opposite function to SMURF1.

SUMMARYWe investigated whether inhibitory natural killer cell receptor (iNKR) expression contributes to impaired antigen-specific cytotoxicity and interferon-c (IFN-c) production by CD8 T cells during chronic infection. iNKR immunoglobulin-like transcript-2 (ILT2 ⁄ CD85j) is expressed on 40-55% of cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)-and human immunodeficiency virus (HIV)-specific CD8 T cells in both healthy and HIV-infected donors. Other iNKRs (CD158a, b1, e1 ⁄ e2, k, CD94 ⁄ NKG2A) are expressed on only a small minority of CD8 T cells and are not preferentially expressed on tetramer-staining virus-specific cells. In normal donors, ILT2 is expressed largely on perforin + CD27 -effector cells. However, in HIV-infected donors, only a third of ILT2 + cells are also perforin + . In both normal and HIV-infected donors, ILT2 + cells are prone to spontaneous apoptosis. Therefore, ILT2 is normally expressed during effector cytotoxic T-lymphocyte (CTL) differentiation, but can also be expressed when effector maturation is incomplete, as in HIV infection. The effect of ILT2 on CD8 cell function was assessed by preincubating effector cells with ILT2 antibody. While blocking ILT2 engagement has no appreciable effect on cytotoxicity, it increases antiviral IFN-c production by approximately threefold in both normal and HIV-infected donors. Thus, ILT2 expression, increased on antiviral CD8 cells in chronic infection, may interfere with protective CD8 T-cell function by suppressing IFN-c production.