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1.
High-level HIV-1 viremia suppresses viral antigen-specific CD4+ T cell proliferation 总被引:1,自引:0,他引:1
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Andrew C. McNeil W. Lesley Shupert Christiana A. Iyasere Claire W. Hallahan JoAnn Mican Richard T. Davey Jr. Mark Connors 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(24):13878-13883
In chronic viral infections of humans and experimental animals, virus-specific CD4(+) T cell function is believed to be critical for induction and maintenance of host immunity that mediates effective restriction of viral replication. Because in vitro proliferation of HIV-specific memory CD4(+) T cells is only rarely demonstrable in HIV-infected individuals, it is presumed that HIV-specific CD4(+) T cells are killed upon encountering the virus, and maintenance of CD4(+) T cell responses in some patients causes the restriction of virus replication. In this study, proliferative responses were absent in patients with poorly restricted virus replication although HIV-specific CD4(+) T cells capable of producing IFN-gamma were detected. In a separate cohort, interruption of antiretroviral therapy resulted in the rapid and complete abrogation of virus-specific proliferation although HIV-1-specific CD4(+) T cells were present. HIV-specific proliferation returned when therapy was resumed and virus replication was controlled. Further, HIV-specific CD4(+) T cells of viremic patients could be induced to proliferate in response to HIV antigens when costimulation was provided by anti-CD28 antibody in vitro. Thus, HIV-1-specific CD4(+) T cells persist but remain poorly responsive (produce IFN-gamma but do not proliferate) in viremic patients. Unrestricted virus replication causes diminished proliferation of virus-specific CD4(+) T cells. Suppression of proliferation of HIV-specific CD4(+) T cells in the context of high levels of antigen may be a mechanism by which HIV or other persistently replicating viruses limit the precursor frequency of virus-specific CD4(+) T cells and disrupt the development of effective virus-specific immune responses. 相似文献
2.
CXCR4 utilization is sufficient to trigger CD4+ T cell depletion in HIV-1-infected human lymphoid tissue
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Michael L. Penn Jean-Charles Grivel Birgit Schramm Mark A. Goldsmith Leonid Margolis 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(2):663-668
The human chemokine receptors CCR5 and CXCR4 have emerged as the predominant cofactors, along with CD4, for cellular entry of HIV-1 in vivo whereas the contribution of other chemokine receptors to HIV disease has not been yet determined. CCR5-specific (R5) viruses predominate during primary HIV-1 infection whereas viruses with specificity for CXCR4 (R5/X4 or X4 viruses) often emerge in late stages of HIV disease. The evolution of X4 viruses is associated with a rapid decline in CD4+ T cells, although a causative relationship between viral tropism and CD4+ T cell depletion has not yet been proven. To rigorously test this relationship, we assessed CD4+ T cell depletion in suspensions of human peripheral blood mononuclear cells and in explants of human lymphoid tissue on exposure to paired viruses that are genetically identical (isogenic) except for select envelope determinants specifying reciprocal tropism for CXCR4 or CCR5. In both systems, X4 HIV-1 massively depleted CD4+ lymphocytes whereas matched R5 viruses depleted such cells only mildly despite comparable viral replication kinetics. These findings demonstrate that the coreceptor specificities of HIV-1 are a causal factor in CD4+ T cell depletion ex vivo and strongly support the hypothesis that the evolution of viral envelope leading to usage of CXCR4 in vivo accelerates loss of CD4+ T cells, causing immunodeficiency. 相似文献
3.
Brd Rsok Jan E. Brinchmann Pl Voltersvik Jan Olofsson Leif Bostad Birgitta sj 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(17):9332-9336
Correlates of virus load and characteristics of virus-producing cells in tonsillar tissue were investigated. Our results suggest that when less than 1:100 tonsillar CD4+ T cells from individuals infected with HIV type-1 (HIV-1) contain replication competent provirus, the level of CD4+ T cells in tonsils is comparable to that observed in uninfected individuals. Virus load at or above this level was associated with low CD4 cell numbers in tonsillar tissue. Only a few percent of all infected T cells in tonsillar tissue were active virus producers, with minor differences observed between individuals. Plasma viremia was found to correlate with infectious virus load in tonsillar tissue. With less than 1:1,000 of CD4 cells in lymphoid tissues being involved in active virus production, direct cytopathic effect by HIV-1 on infected CD4 cells is unlikely to fully explain the immunodeficiency seen in AIDS. 相似文献
4.
The CXC chemokine stromal cell-derived factor 1 is not responsible for CD8+ T cell suppression of syncytia-inducing strains of HIV-1
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Simon F. Lacey Charlene B. McDanal Richard Horuk Michael L. Greenberg 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(18):9842-9847
5.
Kinetics of T cell receptor β, γ, and δ rearrangements during adult thymic development: T cell receptor rearrangements are present in CD44+CD25+ Pro-T thymocytes
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Myriam Capone Richard D. Hockett Jr. Albert Zlotnik 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(21):12522-12527
We performed a comprehensive analysis of T cell receptor (TCR) γ rearrangements in T cell precursors of the mouse adult thymus. Using a sensitive quantitative PCR method, we show that TCRγ rearrangements are present in CD44+CD25+ Pro-T thymocytes much earlier than expected. TCRγ rearrangements increase significantly from the Pro-T to the CD44−CD25+ Pre-T cell transition, and follow different patterns depending on each Vγ gene segment, suggesting that ordered waves of TCRγ rearrangement exist in the adult mouse thymus as has been described in the fetal mouse thymus. Recombinations of TCRγ genes occur concurrently with TCRδ and D-Jβ rearrangements, but before Vβ gene assembly. Productive TCRγ rearrangements do not increase significantly before the Pre-T cell stage and are depleted in CD4+CD8+ double-positive cells from normal mice. In contrast, double-positive thymocytes from TCRδ−/− mice display random proportions of TCRγ rearranged alleles, supporting a role for functional TCRγ/δ rearrangements in the γδ divergence process. 相似文献
6.
Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection
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Giuseppe Pantaleo Hugo Soudeyns James F. Demarest Mauro Vaccarezza Cecilia Graziosi Stefania Paolucci MaryBeth Daucher Oren J. Cohen Franois Denis William E. Biddison Rafick P. Sekaly Anthony S. Fauci 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(18):9848-9853
Down-regulation of the initial burst of viremia during primary HIV infection is thought to be mediated predominantly by HIV-specific cytotoxic T lymphocytes, and the appearance of this response is associated with major perturbations of the T cell receptor repertoire. Changes in the T cell receptor repertoire of virus-specific cytotoxic T lymphocytes were analyzed in patients with primary infection to understand the failure of the cellular immune response to control viral spread and replication. This analysis demonstrated that a significant number of HIV-specific T cell clones involved in the primary immune response rapidly disappeared. The disappearance was not the result of mutations in the virus epitopes recognized by these clones. Evidence is provided that phenomena such as high-dose tolerance or clonal exhaustion might be involved in the disappearance of these monoclonally expanded HIV-specific cytotoxic T cell clones. These findings should provide insights into how HIV, and possibly other viruses, elude the host immune response during primary infection. 相似文献
7.
An enhancer-blocking element between α and δ gene segments within the human T cell receptor α/δ locus
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Xiao-Ping Zhong Michael S. Krangel 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(10):5219-5224
T cell receptor (TCR) α and δ gene segments are organized within a single genetic locus but are differentially regulated during T cell development. An enhancer-blocking element (BEAD-1, for blocking element alpha/delta 1) was localized to a 2.0-kb region 3′ of TCR δ gene segments and 5′ of TCR α joining gene segments within this locus. BEAD-1 blocked the ability of the TCR δ enhancer (Eδ) to activate a promoter when located between the two in a chromatin-integrated construct. We propose that BEAD-1 functions as a boundary that separates the TCR α/δ locus into distinct regulatory domains controlled by Eδ and the TCR α enhancer, and that it prevents Eδ from opening the chromatin of the TCR α joining gene segments for VDJ recombination at an early stage of T cell development. 相似文献
8.
Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection 总被引:7,自引:0,他引:7
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Michihiro Iwashiro Ronald J. Messer Karin E. Peterson Ingunn M. Stromnes Tomoharu Sugie Kim J. Hasenkrug 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(16):9226-9230
Normal levels of CD4(+) regulatory T cells are critical for the maintenance of immunological homeostasis and the prevention of autoimmune diseases. However, we now show that the expansion of CD4(+) regulatory T cells in response to a chronic viral infection can lead to immunosuppression. Mice persistently infected with Friend retrovirus develop approximately twice the normal percentage of splenic CD4(+) regulatory T cells and lose their ability to reject certain tumor transplants. The role of CD4(+) regulatory T cells was demonstrated by the transmission of immunosuppression to uninfected mice by adoptive transfers of CD4(+) T cells. CD4(+) T cells from chronically infected mice were also immunosuppressive in vitro, inhibiting the generation of cytolytic T lymphocytes in mixed lymphocyte cultures. Inhibition occurred at the level of blast-cell formation through a mechanism or mechanisms involving transforming growth factor-beta and the cell surface molecule CTLA-4 (CD152). These results suggest a possible explanation for HIV- and human T cell leukemia virus-I-induced immunosuppression in the absence of T cell depletion. 相似文献
9.
Increased rates of CD4+ and CD8+ T lymphocyte turnover in simian immunodeficiency virus-infected macaques
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Michael Rosenzweig MaryAnn DeMaria David M. Harper Stuart Friedrich Rakesh K. Jain R. Paul Johnson 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(11):6388-6393
Defining the rate at which T cells turn over has important implications for our understanding of T lymphocyte homeostasis and AIDS pathogenesis, yet little information on T cell turnover is available. We used the nucleoside analogue bromodeoxyuridine (BrdUrd) in combination with five-color flow cytometric analysis to evaluate T lymphocyte turnover rates in normal and simian immunodeficiency virus (SIV)-infected rhesus macaques. T cells in normal animals turned over at relatively rapid rates, with memory cells turning over more quickly than naive cells. In SIV-infected animals, the labeling and elimination rates of both CD4+ and CD8+ BrdUrd-labeled cells were increased by 2- to 3-fold as compared with normal controls. In normal and SIV-infected animals, the rates of CD4+ T cell BrdUrd-labeling and decay were closely correlated with those of CD8+ T cells. The elimination rate of BrdUrd-labeled cells was accelerated in both naive and memory T lymphocytes in SIV-infected animals. Our results provide direct evidence for increased rates of both CD4+ and CD8+ T cell turnover in AIDS virus infection and have important implications for our understanding of T cell homeostasis and the mechanisms responsible for CD4+ T cell depletion in AIDS. 相似文献
10.
Christina Berndt Barbara Mpps Sabine Angermüller Peter Gierschik Peter H. Krammer 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(21):12556-12561
AIDS is characterized by a progressive decrease of CD4+ helper T lymphocytes. Destruction of these cells may involve programmed cell death, apoptosis. It has previously been reported that apoptosis can be induced even in noninfected cells by HIV-1 gp120 and anti-gp120 antibodies. HIV-1 gp120 binds to T cells via CD4 and the chemokine coreceptor CXCR4 (fusin/LESTR). Therefore, we investigated whether CD4 and CXCR4 mediate gp120-induced apoptosis. We used human peripheral blood lymphocytes, malignant T cells, and CD4/CXCR4 transfectants, and found cell death induced by both cell surface receptors, CD4 and CXCR4. The induced cell death was rapid, independent of known caspases, and lacking oligonucleosomal DNA fragmentation. In addition, the death signals were not propagated via p56lck and Giα. However, the cells showed chromatin condensation, morphological shrinkage, membrane inversion, and reduced mitochondrial transmembrane potential indicative of apoptosis. Significantly, apoptosis was exclusively observed in CD4+ but not in CD8+ T cells, and apoptosis triggered via CXCR4 was inhibited by stromal cell-derived factor-1, the natural CXCR4 ligand. Thus, this mechanism of apoptosis might contribute to T cell depletion in AIDS and might have major implications for therapeutic intervention. 相似文献
11.
Jesús Gonzlez-Cabrero Catherine J. Wise Yvette Latchman Gordon J. Freeman Arlene H. Sharpe Hans Reiser 《Proceedings of the National Academy of Sciences of the United States of America》1999,96(3):1019-1023
We have generated mice deficient in the expression of the lymphocyte cell surface antigen CD48 (Blast-1, BCM1, sgp-60) by gene targeting in embryonic stem cells. Mice homozygous for the CD48 mutation (CD48−/− mice) are severely impaired in CD4+ T cell activation. Proliferative responses to mitogens, anti-CD3 mAb, and alloantigen are all reduced. Experiments in which T cells and antigen-presenting cells from either wild-type or CD48−/− mice were cocultured reveal that CD48 is important on both T cells and antigen-presenting cells. The most dramatic impairment was observed in experiments in which highly purified T cells were stimulated through the T cell receptor in the presence of the phorbol ester, phorbol 12-myristate 13-acetate. The results of these experiments raise the possibility that CD48 plays a role in signaling through the T cell receptor. 相似文献
12.
In differentiated CD4+ T Cells, interleukin 4 production is cytokine-autonomous, whereas interferon γ production is cytokine-dependent
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Jane Hu-Li Hua Huang John Ryan William E. Paul 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(7):3189-3194
CD4+ T cells from T cell receptor transgenic mice that have been vigorously primed to be interleukin (IL)-4 producers (TH2 cells) are capable of producing IL-4 even if restimulated in the absence of IL-4 and in the presence of IL-12. T cells vigorously primed in the absence of IL-4 (TH1 cells) fail to produce IL-4 even if restimulated under conditions that would cause a naive T cell to produce IL-4. In contrast, interferon γ (IFN-γ) production is highly cytokine-regulated. T cells primed in the presence of IL-4 develop into IFN-γ producers if IFN-γ is included in the priming culture and if the cells are challenged in the presence of IL-12, presumably reflecting the role of IFN-γ in inducing responsiveness to IL-12. Cells primed in the absence of IL-4 become highly responsive to IL-12 if IFN-γ is included in the priming culture, and these cells are excellent IFN-γ producers upon challenge; IL-12 considerably enhances their production of IFN-γ. If cells are primed in the absence of IL-4 and IFN-γ, they show very weak responsiveness to IL-12 as determined by STAT-4 activation. However, these cells acquire IL-12 responsiveness if cultured with IFN-γ for a period as short as 4 hr. Thereafter, they produce large amounts of IFN-γ upon challenge with antigen in the presence of IL-12. These results indicate that in primed CD4+ T cells, IL-4 production is largely cytokine-autonomous, whereas IFN-γ production is highly cytokine-regulated. 相似文献
13.
CCAAT/enhancer binding protein (C/EBP) sites are required for HIV-1 replication in primary macrophages but not CD4+ T cells
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A. J. Henderson K. L. Calame 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(16):8714-8719
The importance of CCAAT/enhancer binding proteins (C/EBPs) and binding sites for HIV-1 replication in primary macrophages, T cell lines and primary CD4+ T cells was examined. When lines overexpressing the C/EBP dominant-negative protein LIP were infected with HIV-1, replication occurred in Jurkat T cells but not in U937 promonocytes, demonstrating a requirement for C/EBP activators by HIV-1 only in promonocytes. Primary macrophages did not support the replication of HIV-1 harboring mutant C/EBP binding sites in the long terminal repeat but Jurkat, H9 and primary CD4+ T cells supported replication of wild-type and mutant HIV-1 equally well. Thus the requirement for C/EBP sites is also confined to monocyte/macrophages. The requirement for C/EBP proteins and sites identifies the first uniquely macrophage-specific regulatory mechanism for HIV-1 replication. 相似文献
14.
An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice
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Nancy Noben-Trauth Leonard D. Shultz Frank Brombacher Joseph F. Urban Jr. Hua Gu William E. Paul 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(20):10838-10843
IL-4 receptor α chain (IL-4Rα)-deficient mice were generated by gene-targeting in BALB/c embryonic stem cells. Mutant mice showed a loss of IL-4 signal transduction and functional activity. The lack of IL-4Rα resulted in markedly diminished, but not absent, TH2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis. CD4+, CD62L-high, and CD62L-low T cell populations from uninfected IL-4Rα−/− mice were isolated by cell sorting. Upon primary stimulation by T cell receptor cross-linkage, the CD62L-low, but not the CD62L-high, cells secreted considerable amounts of IL-4, which was strikingly enhanced upon 4-day culture with anti-CD3 in the presence or absence of IL-4. CD62L-low cells isolated from IL-4Rα−/−, β2-microglobulin−/− double homozygous mice produced less IL-4 than did either IL-4Rα−/− or wild-type mice. These results indicate that an IL-4-independent, β2-microglobulin-dependent pathway exists through which the CD62L-low CD4+ population has acquired IL-4-producing capacity in vivo, strongly suggesting that these cells are NK T cells. 相似文献
15.
F. Cacace G. de Petris F. Pepi 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(8):3507-3512
A scale of relative gas-phase NO+ binding energies (BEs) has been constructed by evaluation of NO+-transfer equilibria L1NO+ + L2 L2NO+ + L1 by Fourier-transform ion cyclotron resonance mass spectrometry and by application of the kinetic method, based on the metastable fragmentation of L1(NO+)L2 nitryl-ion bound dimers. The relative scale, anchored to the NO+ affinity of water, for 52 ligands, including alkyl halides, alkyl nitrates, alcohols, nitroalkanes, nitriles, aldehydes, ketones, and aromatic and heterocyclic compounds, led to an absolute NO+ affinity scale. The results are compared with those of an earlier study, and the apparent discrepancies are traced to a different choice of the absolute BE value used as the reference standard. The NO+ BEs fit a satisfactorily linear correlation when plotted versus the corresponding proton affinities (PAs). The NO+ BEs, while much lower than the PAs, are nevertheless higher than the corresponding BEs of the strictly related NO2+ cation, a result consistent with the experimental and theoretical results currently available on the structure and the stability of NO+ and NO2+ complexes. The NO+ BE vs. PA correlation allows one to estimate within 1–2 kcal·mol−1 the NO+ BE of the molecules included in the comprehensive PA compilations currently available. For example, the correlation gives the following NO+ affinities of the DNA bases, in kcal·mol−1 (1 kcal = 4.18 kJ): adenine, 40.3; cytosine, 40.4; guanine, 40.1; and thymine, 34.9. The experimental NO+ BE of thymine, the only one accessible to direct measurement, amounts to 35.6 ± 2 kcal·mol−1, which underlines the predictive value of the correlation. This study reports the second successful extension of the kinetic method to the evaluation of the absolute BEs of polyatomic cations, following our recent application to the strictly related NO2+ ion. 相似文献
16.
T cell vaccination induces T cell receptor Vβ-specific Qa-1-restricted regulatory CD8+ T cells
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Hong Jiang Helena Kashleva Li-Xing Xu James Forman Lorraine Flaherty Benvenuto Pernis Ned S. Braunstein Leonard Chess 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(8):4533-4537
Vaccination of mice with activated autoantigen-reactive CD4+ T cells (T cell vaccination, TCV) has been shown to induce protection from the subsequent induction of a variety of experimental autoimmune diseases, including experimental allergic encephalomyelitis (EAE). Although the mechanisms involved in TCV-mediated protection are not completely known, there is some evidence that TCV induces CD8+ regulatory T cells that are specific for pathogenic CD4+ T cells. Previously, we demonstrated that, after superantigen administration in vivo, CD8+ T cells emerge that preferentially lyse and regulate activated autologous CD4+ T cells in a T cell receptor (TCR) Vβ-specific manner. This TCR Vβ-specific regulation is not observed in β2-microglobulin-deficient mice and is inhibited, in vitro, by antibody to Qa-1. We now show that similar Vβ8-specific Qa-1-restricted CD8+ T cells are also induced by TCV with activated CD4+ Vβ8+ T cells. These CD8+ T cells specifically lyse murine or human transfectants coexpressing Qa-1 and murine TCR Vβ8. Further, CD8+ T cell hybridoma clones generated from B10.PL mice vaccinated with a myelin basic protein-specific CD4+Vβ8+ T cell clone specifically recognize other CD4+ T cells and T cell tumors that express Vβ8 and the syngeneic Qa-1a but not the allogeneic Qa-1b molecule. Thus, Vβ-specific Qa-1-restricted CD8+ T cells are induced by activated CD4+ T cells. We suggest that these CD8+ T cells may function to specifically regulate activated CD4+ T cells during immune responses. 相似文献
17.
CD8+ T-cell-derived soluble factor(s), but not
β-chemokines RANTES, MIP-1α, and MIP-1β, suppress HIV-1
replication in monocyte/macrophages
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Hiroyuki Moriuchi Masako Moriuchi Christophe Combadiere PhilipM. Murphy AnthonyS. Fauci 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(26):15341-15345
It has been demonstrated that CD8+ T cells produce a soluble factor(s) that suppresses human immunodeficiency virus (HIV) replication in CD4+ T cells. The role of soluble factors in the suppression of HIV replication in monocyte/macrophages (M/M) has not been fully delineated. To investigate whether a CD8+ T-cell-derived soluble factor(s) can also suppress HIV infection in the M/M system, primary macrophages were infected with the macrophage tropic HIV-1 strain Ba-L. CD8+ T-cell-depleted peripheral blood mononuclear cells were also infected with HIV-1 IIIB or Ba-L. HIV expression from the chronically infected macrophage cell line U1 was also determined in the presence of CD8+ T-cell supernatants or β-chemokines. We demonstrate that: (i) CD8+ T-cell supernatants did, but β-chemokines did not, suppress HIV replication in the M/M system; (ii) antibodies to regulated on activation normal T-cell expressed and Secreted (RANTES), macrophage inflammatory protein 1α (MIP-1α) and MIP-1β did not, whereas antibodies to interleukin 10, interleukin 13, interferon α, or interferon γ modestly reduced anti-HIV activity of the CD8+ T-cell supernatants; and (iii) the CD8+ T-cell supernatants did, but β-chemokines did not, suppress HIV-1 IIIB replication in peripheral blood mononuclear cells as well as HIV expression in U1 cells. These results suggest that HIV-suppressor activity of CD8+ T cells is a multifactorial phenomenon, and that RANTES, MIP-1α, and MIP-1β do not account for the entire scope of CD8+ T-cell-derived HIV-suppressor factors. 相似文献
18.
CC-chemokines enhance the replication of T-tropic strains of HIV-1 in CD4+ T Cells: Role of signal transduction
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Audrey Kinter Andrew Catanzaro JoAn Monaco Margaret Ruiz Jesse Justement Susan Moir James Arthos Alessandra Oliva Linda Ehler Stephanie Mizell Robert Jackson Mario Ostrowski James Hoxie Robin Offord Anthony S. Fauci 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(20):11880-11885
This study demonstrates that several CC-chemokines, including those that inhibit entry and replication of macrophage-tropic strains of HIV, increase the replication of T cell (T)-tropic strains in CD4+ T cells. Enhancement of T-tropic HIV replication is observed at early stages of replication, requires signaling through inhibitory guanine nucleotide-binding regulatory (Gi) proteins, and is associated with increased cell surface colocalization of CD4 and the T-tropic HIV coreceptor CXCR4. These findings may further our understanding of the factors that influence the replication and spread of T-tropic strains of HIV in vivo and suggest that the use of cell signaling CC-chemokines as therapeutic agents for the purpose of limiting HIV replication in vivo should be approached with caution. 相似文献
19.
DonaldD.F. Loo Thomas Zeuthen Grischa Chandy ErnestM. Wright 《Proceedings of the National Academy of Sciences of the United States of America》1996,93(23):13367-13370
Water is transported across epithelial membranes in the absence of any hydrostatic or osmotic gradients. A prime example is the small intestine, where 10 liters of water are absorbed each day. Although water absorption is secondary to active solute transport, the coupling mechanism between solute and water flow is not understood. We have tested the hypothesis that water transport is directly linked to solute transport by cotransport proteins such as the brush border Na+/glucose cotransporter. The Na+/glucose cotransporter was expressed in Xenopus oocytes, and the changes in cell volume were measured under sugar-transporting and nontransporting conditions. We demonstrate that 260 water molecules are directly coupled to each sugar molecule transported and estimate that in the human intestine this accounts for 5 liters of water absorption per day. Other animal and plant cotransporters such as the Na+/Cl−/γ-aminobutyric acid, Na+/iodide and H+/amino acid transporters are also able to transport water and this suggests that cotransporters play an important role in water homeostasis. 相似文献
20.
Development and function of T cells in T cell antigen
receptor/CD3 ζ knockout mice reconstituted with FcɛRI γ
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Chih-Pin Liu Wei-Jen Lin Manley Huang John W. Kappler Philippa Marrack 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(2):616-621
Engagement of α–β T cell receptors (TCRs) induces many events in the T cells bearing them. The proteins that transduce these signals to the inside of cells are the TCR-associated CD3 polypeptides and ζ–ζ or ζ–η dimers. Previous experiments using knockout (KO) mice that lacked ζ (ζKO) showed that ζ is required for good surface expression of TCRs on almost all T cells and for normal T cell development. Surprisingly, however, in ζKO mice, a subset of T cells in the gut of both ζKO and normal mice bore nearly normal levels of TCR on its surface. This was because ζ was replaced by the FcRI γ (FcRγ). These cells were relatively nonreactive to stimuli via their TCRs. In addition, a previous report showed that ζ replacement by the FcRγ chain also might occur on T cells in mice bearing tumors long term. Again, these T cells were nonreactive. To understand the consequences of ζ substitution by FcRγ for T cell development and function in vivo, we produced ζKO mice expressing FcRγ in all of their T cells (FcRγTG ζKO mice). In these mice, TCR expression on immature thymocytes was only slightly reduced compared with controls, and thymocyte selection occurred normally and gave rise to functional, mature T cells. Therefore, the nonreactivity of the FcRγ+ lymphocytes in the gut or in tumor-bearing mice must be caused by some other phenomenon. Unexpectedly, the TCR levels of mature T cells in FcRγTG ζKO mice were lower than those of controls. This was particularly true for the CD4+ T cells. We conclude that FcRγ can replace the functions of ζ in T cell development in vivo but that TCR/CD3 complexes associated with FcRγ rather than ζ are less well expressed on cells. Also, these results revealed a difference in the regulation of expression of the TCR/CD3 complex on CD4+ and CD8+ T cells. 相似文献