CD45在T细胞激活过程中的作用

CD4 5是免疫系统主要的跨膜酪氨酸磷酸酶 ,已经形成的共识认为 ,CD4 5在信号转导过程中单一的起着正调节作用 ,促进了生命信号向细胞内的传播 .模型阐述了CD4 5在信号过程中的双重作用 ,为近期的的试验提供了理论解释 .

Molecular mechanisms of triggering,amplifying and targeting RANK signaling in osteoclasts

Osteoclast differentiation depends on receptor activator of nuclear factor-κB(RANK) signaling,which can be divided into triggering,amplifying and targeting phases based on how active the master regulator nuclear factor of activated T-cells cytoplasmic 1(NFATc1) is. The triggering phase is characterized by immediateearly RANK signaling induced by RANK ligand(RANKL) stimulation mediated by three adaptor proteins,tumor necrosis factor receptor-associated factor 6,Grb-2-associated binder-2 and phospholipase C(PLC)γ2,leading to activation of IκB kinase,mitogen-activated protein kinases and the transcription factors nuclear factor(NF)-κB and activator protein-1(AP-1). Mice lacking NF-κB p50/p52 or the AP-1 subunit c-Fos(encoded by Fos) exhibit severe osteopetrosis due to a differentiation block in the osteoclast lineage. The amplification phase occurs about 24 h later in a RANKLinduced osteoclastogenic culture when Ca2+ oscillation starts and the transcription factor NFATc1 is abundantly produced. In addition to Ca2+ oscillation-dependent nuclear translocation and transcriptional auto-induction of NFATc1,a Ca2+ oscillation-independent,osteoblastdependent mechanism stabilizes NFATc1 protein in dif-ferentiating osteoclasts. Osteoclast precursors lacking PLCγ2,inositol-1,4,5-trisphosphate receptors,regulator of G-protein signaling 10,or NFATc1 show an impaired transition from the triggering to amplifying phases. The final targeting phase is mediated by activation of numerous NFATc1 target genes responsible for cell-cell fusion and regulation of bone-resorptive function. This review focuses on molecular mechanisms for each of the three phases of RANK signaling during osteoclast differentiation.

ZAP-70在ITAM活化中的作用

在假设ITAM两步磷酸化的基础上 ,建立理论模型 ,定性讨论了ZAP 70在ITAM活化中的作用 .结果表明 :TCR与MHC pep抗原多肽的亲和力是影响免疫应答的一个重要参数 ,但ZAP 70对ITAM活化事件的正反馈调节会使得TCR对特异性抗原识别的敏锐性降低 ,当这种调节达到一定程度时 ,免疫应答将不再依赖抗原的特异性 .进一步讨论了半活化状态的ZAP 70的作用 ,运用此模型还解释了ITAM的活化过程存在一个ITAM/ZAP 70的浓度阈值问题 .

Changing roles of CD3^(+)CD8^(low) T cells in combating HIV-1 infection

Background:Cluster of differentiation 8(CD8 T)cells play critical roles in eradicating human immunodeficiency virus(HIV)-1 infection,but little is known about the effects of T cells expressing CD8 at low levels(CD8^(low))or high levels(CD8^(high))on HIV-1 replication inhibition after HIV-1 invasion into individual.Methods:Nineteen patients who had been acutely infected with HIV-1(AHI)and 20 patients with chronic infection(CHI)for≥2 years were enrolled in this study to investigate the dynamics of the quantity,activation,and immune responses of CD3^(+)CD8^(low) T cells and their counterpart CD3^(+)CD8^(high) T cells at different stages of HIV-1 infection.Results:Compared with healthy donors,CD3^(+)CD8^(low) T cells expanded in HIV-1-infected individuals at different stages of infection.As HIV-1 infection progressed,CD3^(+)CD8^(low) T cells gradually decreased.Simultaneously,CD3^(+)CD8^(high) T cells was significantly reduced in the first month of AHI and then increased gradually as HIV-1 infection progressed.The classical activation of CD3^(+)CD8^(low) T cells was highest in the first month of AHI and then reduced as HIV-1 infection progressed and entered the chronic stage.Meanwhile,activated CD38^(-)HLA-DR^(+)CD8^(low) T cells did not increase in the first month of AHI,and the number of these cells was inversely associated with viral load(r=-0.664,P=0.004)but positively associated with the CD4 T-cell count(r=0.586,P=0.014).Increased programmed cell death protein 1(PD-1)abundance on CD3^(+)CD8^(low) T cells was observed from the 1st month of AHI but did not continue to be enhanced,while a significant T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif(ITIM)domains(TIGIT)abundance increase was observed in the 12th month of infection.Furthermore,increased PD-1 and TIGIT abundance on CD3^(+)CD8^(low) T cells was associated with a low CD4 T-cell count(PD-1:r=-0.456,P=0.043;TIGIT:r=-0.488,P=0.029)in CHI.Nonetheless,the nonincrease in PD-1 expression on classically activated CD3^(+)CD8^(low) T cells was inversely associated with HIV-1 viremia in the first month of AHI(r=-0.578,P=0.015).Notably,in the first month of AHI,few CD3^(+)CD8^(low) T cells,but comparable amounts of CD3^(+)CD8^(high) T cells,responded to Gag peptides.Then,weaker HIV-1-specific T-cell responses were induced in CD3^(+)CD8^(low) T cells than CD3^(+)CD8^(high) T cells at the 3rd and 12th months of AHI and in CHI.Conclusions:Our findings suggest that CD3^(+)CD8^(low) T cells play an anti-HIV role in the first month of infection due to their abundance but induce a weak HIV-1-specific immune response.Subsequently,CD3^(+)CD8^(low) T-cell number decreased gradually as infection persisted,and their anti-HIV functions were inferior to those of CD3^(+)CD8^(high) T cells.

CpG-ODN在T细胞活化和抑制中的作用

CpG-ODN 是人工合成的含有 CpG 基序的 ODNs,能够模拟细菌 DNA 的免疫刺激活性,通过细胞内定位的 Toll 样受体9活化抗原递呈细胞(APC),如树突状细胞(DC)和 B 细胞,分泌大量 Th1型细胞因子诱导产生 Th1型免疫应答。CpG-ODN 不仅增强 T 淋巴细胞的活化,在特定条件下还可以抑制 T 淋巴细胞功能。在抗感染、抗肿瘤疾病中,CpG-ODN 作为新型的免疫佐剂得到了广泛的应用,但其安全性问题应引起足够的重视。