Collaborative Innovation Center for Infectious Diseases

Hangzhou, China

Collaborative Innovation Center for Infectious Diseases

Hangzhou, China
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Zeng Y.,Tsinghua University | Zeng Y.,Collaborative Innovation Center for Infectious Diseases | Yi J.,Tsinghua University | Yi J.,Collaborative Innovation Center for Infectious Diseases | And 12 more authors.
European Journal of Immunology | Year: 2015

B cells use B-cell receptors (BCRs) to sense antigens that are usually presented on substrates with different stiffness. However, it is not known how substrate stiffness affects B-cell proliferation, class switch, and in vivo antibody responses. We addressed these questions using polydimethylsiloxane (PDMS) substrates with different stiffness (20 or 1100 kPa). Live cell imaging experiments suggested that antigens on stiffer substrates more efficiently trigger the synaptic accumulation of BCR and phospho-Syk molecules compared with antigens on softer substrates. In vitro expansion of mouse primary B cells shows different preferences for substrate stiffness when stimulated by different expansion stimuli. LPS equally drives B-cell proliferation on stiffer or softer substrates. Anti-CD40 antibodies enhance B-cell proliferation on stiffer substrates, while antigens enhance B-cell proliferation on softer substrates through a mechanism involving the enhanced phosphorylation of PI3K, Akt, and FoxO1. In vitro class switch differentiation of B cells prefers softer substrates. Lastly, NP67-Ficoll on softer substrates accounted for an enhanced antibody response in vivo. Thus, substrate stiffness regulates B-cell activation, proliferation, class switch, and T cell independent antibody responses in vivo, suggesting its broad application in manipulating the fate of B cells in vitro and in vivo. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Jia Z.,Peking University | Jia Z.,Takemi Program in International Health | Mao Y.,National Center for Control and Prevention | Zhang F.,National Center for Control and Prevention | And 28 more authors.
The Lancet | Year: 2013

Background: On the basis of the results of the randomised clinical trial HPTN 052 and observational studies, WHO has recommended that antiretroviral therapy be offered to all HIV-infected individuals with uninfected partners of the opposite sex (serodiscordant couples) to reduce the risk of transmission. Whether or not such a public health approach is feasible and the outcomes are sustainable at a large scale and in a developing country setting has not previously been assessed. Methods In this retrospective observational cohort study, we included treated and treatment-naive HIV-positive individuals with HIV-negative partners of the opposite sex who had been added to the national HIV epidemiology and treatment databases between Jan 1, 2003 and Dec 31, 2011. We analysed the annual rate of HIV infection in HIV negative partners during follow-up, stratified by treatment status of the index partner. Cox proportional hazards analyses were done to examine factors related to HIV transmission. Findings Based on data from 38 862 serodiscordant couples, with 101 295 1 person-years of follow-up for the seronegative partners, rates of HIV infection were 2 6 per 100 person-years (95% CI 2 4-2 8) among the 14 805 couples in the treatment-naive cohort (median baseline CD4 count for HIV-positive partners 441 cells per μl [IQR 314-590]) and 1 3 per 100 person-years (1 2-1 3) among the 24 057 couples in the treated cohort (median baseline CD4 count for HIV-positive partners 168 cells per μl [62-269]). We calculated a 26% relative reduction in HIV transmission (adjusted hazard ratio 0 74, 95% CI 0 65-0 84) in the treated cohort. The reduction in transmission was seen across almost all demographic subgroups and was significant in the first year (0 64, 0 54-0 76), and among couples in which the HIV-positive partner had been infected by blood or plasma transfusion (0 76, 0 59-0 99) or heterosexual intercourse (0 69, 0 56-0 84), but not among couples in which the HIV-positive partner was infected by injecting drugs (0 98, 0 71-1 36). Interpretation Antiretroviral therapy for HIV-positive individuals in serodiscordant couples reduced HIV transmission across China, which suggests that the treatment-as-prevention approach is a feasible public health prevention strategy on a national scale in a developing country context. The durability and generalisability of such protection, however, needs to be further studied.

Xu L.,Tsinghua University | Xu L.,Collaborative Innovation Center for Infectious Diseases | Xu L.,Peking Union Medical College | Xu L.,Key Laboratory of Rheumatology and Clinical Immunology | And 12 more authors.
Journal of Leukocyte Biology | Year: 2015

Sphingolipid- and cholesterol-rich lipid raft microdomains are important in the initiation of BCR signaling. Although it is known that lipid rafts promote the coclustering of BCR and Lyn kinase microclusters within the B cell IS, the molecular mechanism of the recruitment of lipid rafts into the B cell IS is not understood completely. Here, we report that the synaptic recruitment of lipid rafts is dependent on the cytoskeleton-remodeling proteins, RhoA and Vav. Such an event is also efficiently regulated by motor proteins, myosin IIA and dynein. Further evidence suggests the synaptic recruitment of lipid rafts is, by principle, an event triggered by BCR signaling molecules and second messenger molecules. BCR-activating coreceptor CD19 potently enhances such an event depending on its cytoplasmic Tyr421 and Tyr482 residues. The enhancing function of the CD19-PI3K module in synaptic recruitment of lipid rafts is also confirmed in human peripheral blood B cells. Thus, these results improve our understanding of the molecular mechanism of the recruitment of lipid raft microdomains in B cell IS. © Society for Leukocyte Biology.

Liu C.,Tsinghua University | Liu C.,Collaborative Innovation Center for Infectious Diseases | Zhao X.W.,Tsinghua University | Xu L.L.,Tsinghua University | And 9 more authors.
Journal of Leukocyte Biology | Year: 2015

Advanced live cell imaging studies suggested that B cell activation is initiated by the formation of BCR microclusters and subsequent B cell IS upon BCR and antigen recognition. PKC family member PKCβ is highly expressed in B cells and plays an important role in the initiation of B cell activation. Here, we reported an inhibitory function of PKCβ through a negative-feedback manner in B cell activation. Compared with WT (PKCβ- WT) or the constitutively active (PKCβ-ΔNPS) form of PKCβ, DN PKCβ (PKCβ-DN) unexpectedly enhanced the accumulation of BCR microclusters into the B cell IS, leading to the recruitment of an excessive amount of pSyk, pPLC-γ2, and pBLNK signaling molecules into the membrane-proximal BCR signalosome. Enhanced calcium mobilization responses in the decay phase were also observed in B cells expressing PKCβ-DN. Mechanistic studies showed that this negative-feedback function of PKCβ works through the induction of an inhibitory form of pBtk at S180 (pBtk-S180). Indeed, the capability of inducing the formation of an inhibitory pBtk-S180 is in the order of PKCβ-ΔNPS. PKCβ-WT. PKCβ-DN. Thus, these results improve our comprehensive understanding on the positive and negative function of PKCβ in the fine tune of B cell activation. © Society for Leukocyte Biology.

Chen X.,Tsinghua University | Chen X.,Collaborative Innovation Center for Infectious Diseases | Li G.,Tsinghua University | Wan Z.,Tsinghua University | And 4 more authors.
Progress in Biophysics and Molecular Biology | Year: 2015

Antibody memory is critical for protection against many human infectious diseases and is the basis for nearly all current human vaccines. Isotype switched immunoglobulin (Ig) G-expressing memory B cells are considered as one of the fundaments for the rapid, high affinity and high-titered memory antibody response. The detailed molecular mechanism of the enhanced activation of IgG-switched memory B cells upon BCR engagement with antigens has been an elusive question in immunology. In this review, we tried to discuss all the exciting new advances revealing the molecular mechanisms of the transmembrane signaling through mIgG cytoplasmic tail in IgG-switched memory B cells. © 2015 Elsevier Ltd.

Zhang S.,Tsinghua University | Xu L.,Tsinghua University | Zhao X.,Tsinghua University | Chen X.,Tsinghua University | And 5 more authors.
PLoS ONE | Year: 2013

Our understanding of cell-cell interactions has been significantly improved in the past years with the help of Total Internal Reflection Fluorescence Microscope (TIRFM) in combination with an antigen presenting system supported by planar lipid bilayer (PLB) membranes, which are used to mimic the extensive receptor and ligand interactions within cell-cell contact interface. In TIRFM experiments, it is a challenge to uniformly present ligand molecules in monomeric format on the surface of PLB membranes. Here, we introduce a new and robust method of tethering IgG surrogate antigen ligands on the surface of Ni2+-containing PLB membranes. In this method, we use a modified D domain from staphylococcal protein A molecule that is fused with an N-terminus polyhistidine tag (H12-D-domain) to tether IgG surrogate antigens on Ni2+-containing PLB membranes. We systematically assessed the specificity and capability of H12-D-domain construct to capture IgG molecules from different species through live cell and single molecule TIRFM imaging. We find that these IgG surrogate antigens tethered by H12-D-domain show better lateral mobility and are more uniformly distributed on PLB membranes than the ones tethered by streptavidin. Neither IgM molecules, nor Fab or F(ab')2 fragments of IgG molecules can be tethered on PLB membranes by H12-D-domain construct. These tethered IgG surrogate antigens strongly induce the formation and accumulation of signaling active antigen receptor microclusters within the immunological synapse in B or T lymphocyte cells. Thus our method provides a new and robust method to tether IgG surrogate antigens or other molecules fused with IgG Fc portion on PLB membranes for TIRFM based molecule imaging experiments. © 2013 Zhang et al.

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