Regulation of cutaneous malignancy by gammadelta T cells

The localization of gammadelta T cells within epithelia suggests that these cells may contribute to the down-regulation of epithelial malignancies. We report that mice lacking gammadelta cells are highly susceptible to multiple regimens of cutaneous carcinogenesis. After exposure to carcinogens, skin cells expressed Rae-1 and H60, major histocompatibility complex-related molecules structurally resembling human MICA. Each of these is a ligand for NKG2d, a receptor expressed by cytolytic T cells and natural killer (NK) cells. In vitro, skin-associated NKG2d+ gammadelta cells killed skin carcinoma cells by a mechanism that was sensitive to blocking NKG2d engagement. Thus, local T cells may use evolutionarily conserved proteins to negatively regulate malignancy.     

A population of murine gammadelta T cells that recognize an inducible MHC class Ib molecule

Although gammadelta T cells are implicated in regulating immune responses, gammadelta T cell-ligand pairs that could mediate such regulatory functions have not been identified. Here, the expression of the major histocompatibility complex (MHC) class Ib T22 and the closely related T10 molecules is shown to be activation-induced, and they confer specificity to about 0.4% of the gammadelta T cells in normal mice. Thus, the increased expression of T22 and/or T10 might trigger immunoregulatory gammadelta T cells during immune responses. Furthermore, the fast on-rates and slow off-rates that characterize this receptor/ligand interaction would compensate for the low ligand stability and suggest a high threshold for gammadelta T cell activation.     

Structure of a gammadelta T cell receptor in complex with the nonclassical MHC T22

Gammadelta T cell receptors (TCRs), alphabeta TCRs, and antibodies are the three lineages of somatically recombined antigen receptors. The structural basis for ligand recognition is well defined for alphabeta TCR and antibodies but is lacking for gammadelta TCRs. We present the 3.4 A structure of the murine gammadelta TCR G8 bound to its major histocompatibility complex (MHC) class Ib ligand, T22. G8 predominantly uses germline-encoded residues of its delta chain complementarity-determining region 3 (CDR3) loop to bind T22 in an orientation substantially different from that seen in alphabeta TCR/peptide-MHC. That junctionally encoded G8 residues play an ancillary role in binding suggests a fusion of innate and adaptive recognition strategies.     

A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory

The delivery of CD4 help to CD8+ T cell responses requires interactions between CD40 and CD40 ligand and is thought to occur through antigen-presenting cell (APC) activation. Here we show that generation of memory CD8+ T cells displaying an enhanced capacity for cell division and cytokine secretion required CD4 help but not CD40 expression by the APCs. Activated CD4+ and CD8+ T cells expressed CD40; and in the absence of this protein, CD8+ T cells were unable to differentiate into memory cells or receive CD4 help. These results suggest that, like B cells, CD8+ T cells receive CD4 help directly through CD40 and that this interaction is fundamental for CD8+ T cell memory generation.     

The role of the T cell receptor in positive and negative selection of developing T cells

Although many combinations of alpha beta T cell receptors are available to the T cells in any given organism, far fewer are actually used by mature T cells. The combinations used are limited by two selective processes, positive selection of T cells bearing receptors that will be useful to the host, and clonal elimination or inactivation of T cells bearing receptors that will be damaging to the host. The ways in which these two apparently contradictory processes occur, and the hypotheses that have been suggested to reconcile them, are discussed.     

The role of B cells for in vivo T cell responses to a Friend virus-induced leukemia

B cells can function as antigen-presenting cells and accessory cells for T cell responses. This study evaluated the role of B cells in the induction of protective T cell immunity to a Friend murine leukemia virus (F-MuLV)-induced leukemia (FBL). B cell-deficient mice exhibited significantly reduced tumor-specific CD4+ helper and CD8+ cytotoxic T cell responses after priming with FBL or a recombinant vaccinia virus containing F-MuLV antigens. Moreover, these mice had diminished T cell responses to the vaccinia viral antigens. Tumor-primed T cells transferred into B cell-deficient mice effectively eradicated disseminated FBL. Thus, B cells appear necessary for efficient priming but not expression of tumor and viral T cell immunity.     

A role for thrombin receptor signaling in endothelial cells during embryonic development

The coagulation protease thrombin triggers fibrin formation, platelet activation, and other cellular responses at sites of tissue injury. We report a role for PAR1, a protease-activated G protein-coupled receptor for thrombin, in embryonic development. Approximately half of Par1-/- mouse embryos died at midgestation with bleeding from multiple sites. PAR1 is expressed in endothelial cells, and a PAR1 transgene driven by an endothelial-specific promoter prevented death of Par1-/- embryos. Our results suggest that the coagulation cascade and PAR1 modulate endothelial cell function in developing blood vessels and that thrombin's actions on endothelial cells-rather than on platelets, mesenchymal cells, or fibrinogen-contribute to vascular development and hemostasis in the mouse embryo.     

A critical role for the innate immune signaling molecule IRAK-4 in T cell activation

IRAK-4 is a protein kinase that is pivotal in mediating signals for innate immune responses. Here, we report that IRAK-4 signaling is also essential for eliciting adaptive immune responses. Thus, in the absence of IRAK-4, in vivo T cell responses were significantly impaired. Upon T cell receptor stimulation, IRAK-4 is recruited to T cell lipid rafts, where it induces downstream signals, including protein kinase C activation through the association with Zap70. This signaling pathway was found to be required for optimal activation of nuclear factor kappaB. Our findings suggest that T cells use this critical regulator of innate immunity for the development of acquired immunity, suggesting that IRAK-4 may be involved in direct signal cross talk between the two systems.     

鱼鳔胶原蛋白-壳聚糖-海藻酸钠水凝胶促小鼠皮肤伤口愈合研究

以鳗鱼（Anguillidae）鱼鳔胶原蛋白为主药,采用Ca²⁺交联法制备水凝胶敷料,利用扫描电镜观察其结构;通过在小鼠背部皮肤制作伤口试验模型,分别用0.9%生理盐水（对照组）和水凝胶敷料（试验组）进行护理,观察3、7、14 d时皮肤伤口的愈合情况,HE染色观察皮肤的组织学变化。结果表明,水凝胶在扫描电镜下呈现多孔隙结构,水凝胶组血清抗氧化能力高于对照组,炎症因子水平低于对照组。水凝胶敷料明显促进伤口愈合,减轻伤口红肿和炎症,皮肤修复完整疤痕较小。     

儿茶素单体对3T3-L1细胞损伤的保护与修复作用

探讨了4种儿茶素单体对Na2S2O4诱导的3T3-L1细胞缺氧损伤和H2O2诱导的细胞氧化损伤的保护与修复作用。体外培养3T3-L1细胞,利用Na2S2O4诱导细胞缺氧损伤和H2O2诱导细胞氧化损伤,采用先加入诱导剂后加入儿茶素单体和先加入儿茶素单体后加入诱导剂两种处理方式,MTT法检测3T3-L1细胞存活率的变化。结果表明,先加入诱导剂可严重损伤3T3-L1细胞,再加入4种儿茶素单体均能对3T3-L1细胞进行修复,显著地提高细胞的存活率;而先加入4种儿茶素单体再加入诱导剂,细胞受损程度则显著降低,表明4种儿茶素单体对3T3-L1细胞缺氧或氧化损伤都具有较好的保护与修复作用。     

罗非鱼皮多肽的制备及其对烫伤修复的应用

以罗非鱼皮为原料,通过酶的筛选和酶解正交试验,分别获得木瓜蛋白酶和碱性蛋白酶酶解罗非鱼皮的最优酶解条件,在两种酶的最优酶解条件下进行分步复合酶解制备罗非鱼皮多肽,并探究罗非鱼皮多肽对新西兰兔皮肤烫伤创面的修复作用。结果表明,木瓜蛋白酶和碱性蛋白酶的最优酶解条件分别为pH6.5、温度55℃、底物浓度30%、酶用量0.5%和pH9.5、温度45℃、底物浓度35%、酶用量0.4%,相应的蛋白质回收率为90.54(±1.72)%和89.22(±2.14)%,复合酶解所得的蛋白质回收率比最优酶解条件下的木瓜蛋白酶和碱性蛋白酶分别提高了5.03%和6.58%。烫伤愈合实验结果表明:伤口处理后17 d,实验组与阳性对照组的创面愈合率均已达到95%以上,与模型对照组相比均有显著性差异;实验组与阳性对照组的创面愈合率未见明显差异,愈合效果相近。病理组织学结果显示,实验组烫伤创面恢复情况最好,表明罗非鱼皮多肽对皮肤烫伤创面有很好的修复效果。     

Potentiation of bleomycin lethality by anticalmodulin drugs: a role for calmodulin in DNA repair

Treatment of exponentially growing Chinese hamster ovary cells with bleomycin causes a dose-dependent decrease in cell survival due to DNA damage. This lethal effect can be potentiated by the addition of a nonlethal dose of the anticalmodulin drug N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide ( W13 ) but not its inactive analog N-(4-aminobutyl)-2-naphthalenesulfonamide ( W12 ). By preventing the repair of damaged DNA, W13 also inhibits recovery from potentially lethal damage induced by bleomycin. These data suggest a role for calmodulin in the DNA repair pathway.     

A proton buffering role for silica in diatoms

For 40 million years, diatoms have dominated the reverse weathering of silica on Earth. These photosynthetic protists take up dissolved silicic acid from the water and precipitate opaline silica to form their cell wall. We show that the biosilica of diatoms is an effective pH buffer, enabling the enzymatic conversion of bicarbonate to CO2, an important step in inorganic carbon acquisition by these organisms. Because diatoms are responsible for one-quarter of global primary production and for a large fraction of the carbon exported to the deep sea, the global cycles of Si and C may be linked mechanistically.     

A role for DNA-PK in retroviral DNA integration

Retroviral DNA integration is catalyzed by the viral protein integrase. Here, it is shown that DNA-dependent protein kinase (DNA-PK), a host cell protein, also participates in the reaction. DNA-PK-deficient murine scid cells infected with three different retroviruses showed a substantial reduction in retroviral DNA integration and died by apoptosis. Scid cell killing was not observed after infection with an integrase-defective virus, suggesting that abortive integration is the trigger for death in these DNA repair-deficient cells. These results suggest that the initial events in retroviral integration are detected as DNA damage by the host cell and that completion of the integration process requires the DNA-PK-mediated repair pathway.