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1.
Traggiai E Chicha L Mazzucchelli L Bronz L Piffaretti JC Lanzavecchia A Manz MG 《Science (New York, N.Y.)》2004,304(5667):104-107
Because ethical restrictions limit in vivo studies of the human hemato-lymphoid system, substitute human to small animal xenotransplantation models have been employed. Existing models, however, sustain only limited development and maintenance of human lymphoid cells and rarely produce immune responses. Here we show that intrahepatic injection of CD34+ human cord blood cells into conditioned newborn Rag2-/-gammac-/- mice leads to de novo development of B, T, and dendritic cells; formation of structured primary and secondary lymphoid organs; and production of functional immune responses. This provides a valuable model to study development and function of the human adaptive immune system in vivo. 相似文献
2.
Savage PA Vosseller K Kang C Larimore K Riedel E Wojnoonski K Jungbluth AA Allison JP 《Science (New York, N.Y.)》2008,319(5860):215-220
Substantial evidence exists that many tumors can be specifically recognized by CD8+ T lymphocytes. The definition of antigens targeted by these cells is paramount for the development of effective immunotherapeutic strategies for treating human cancers. In a screen for endogenous tumor-associated T cell responses in a primary mouse model of prostatic adenocarcinoma, we identified a naturally arising CD8+ T cell response that is reactive to a peptide derived from histone H4. Despite the ubiquitous nature of histones, T cell recognition of histone H4 peptide was specifically associated with the presence of prostate cancer in these mice. Thus, the repertoire of antigens recognized by tumor-infiltrating T cells is broader than previously thought and includes peptides derived from ubiquitous self antigens that are normally sequestered from immune detection. 相似文献
3.
The immune system develops in waves during ontogeny; it is initially populated by cells generated from fetal hematopoietic stem cells (HSCs) and later by cells derived from adult HSCs. Remarkably, the genetic programs that control these two distinct stem cell fates remain poorly understood. We report that Lin28b is specifically expressed in mouse and human fetal liver and thymus, but not in adult bone marrow or thymus. We demonstrate that ectopic expression of Lin28 reprograms hematopoietic stem/progenitor cells (HSPCs) from adult bone marrow, which endows them with the ability to mediate multilineage reconstitution that resembles fetal lymphopoiesis, including increased development of B-1a, marginal zone B, gamma/delta (γδ) T cells, and natural killer T (NKT) cells. 相似文献
4.
Mold JE Venkatasubrahmanyam S Burt TD Michaëlsson J Rivera JM Galkina SA Weinberg K Stoddart CA McCune JM 《Science (New York, N.Y.)》2010,330(6011):1695-1699
Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or "layering") of distinct hematopoietic stem cells (HSCs) that give rise to distinct lymphocyte lineages at different stages of development. Here we provide evidence of an analogous layered immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSCs that are present at different stages of development. We also provide evidence that the fetal T cell lineage is biased toward immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth. 相似文献
5.
Sporozoite vaccine induces genetically restricted T cell elimination of malaria from hepatocytes 总被引：21，自引：0，他引：21
S L Hoffman D Isenbarger G W Long M Sedegah A Szarfman L Waters M R Hollingdale P H van der Meide D S Finbloom W R Ballou 《Science (New York, N.Y.)》1989,244(4908):1078-1081
The target of the CD8+ T cell-dependent immunity that protects mice immunized with irradiation-attenuated malaria sporozoites has not been established. Immune BALB/c mice were shown to develop malaria-specific, CD8+ T cell-dependent inflammatory infiltrates in their livers after challenge with Plasmodium berghei sporozoites. Spleen cells from immune BALB/c and C57BL/6 mice eliminated hepatocytes infected with the liver stage of P. berghei in vitro. The activity against infected hepatocytes is not inhibited by antibodies to interferon-gamma and is not present in culture supernatants. It is genetically restricted, an indication that malaria antigens on the hepatocyte surface are recognized by immune T effector cells. Subunit vaccine development will require identification of the antigens recognized by these T cells and a method of immunization that induces such immunity. 相似文献
6.
Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice 总被引：32，自引：0，他引：32
M J Grusby R S Johnson V E Papaioannou L H Glimcher 《Science (New York, N.Y.)》1991,253(5026):1417-1420
The maturation of T cells in the thymus is dependent on the expression of major histocompatibility complex (MHC) molecules. By disruption of the MHC class II Ab beta gene in embryonic stem cells, mice were generated that lack cell surface expression of class II molecules. These MHC class II-deficient mice were depleted of mature CD4+ T cells and were deficient in cell-mediated immune responses. These results provide genetic evidence that class II molecules are required for the maturation and function of mature CD4+ T cells. 相似文献
7.
Altered K+ channel expression in abnormal T lymphocytes from mice with the lpr gene mutation 总被引：9，自引：0，他引：9
K G Chandy T E DeCoursey M Fischbach N Talal M D Cahalan S Gupta 《Science (New York, N.Y.)》1986,233(4769):1197-1200
The observation that voltage-dependent K+ channels are required for activation of human T lymphocytes suggests that pathological conditions involving abnormal mitogen responses might be reflected in ion channel abnormalities. Gigaohm seal techniques were used to study T cells from MRL/MpJ-lpr/lpr mice; these mice develop generalized lymphoproliferation of functionally and phenotypically abnormal T cells and a disease resembling human systemic lupus erythematosus. The number and predominant type of K+ channels in T cells from these mice differ dramatically from those in T cells from control strains and a congenic strain lacking the lpr gene locus. Thus an abnormal pattern of ion channel expression has now been associated with a genetic defect in cells of the immune system. 相似文献
8.
Interleukin-2 (IL-2), which is a growth factor for T lymphocytes, can also sometimes be inhibitory. Thus, the proliferation of CD8+ T cells in vivo is increased after the injection of a monoclonal antibody that is specific for IL-2 (IL-2 mAb), perhaps reflecting the removal of IL-2-dependent CD4+ T regulatory cells (T regs). Instead, we show here that IL-2 mAb augments the proliferation of CD8+ cells in mice simply by increasing the biological activity of preexisting IL-2 through the formation of immune complexes. When coupled with recombinant IL-2, some IL-2/IL-2 mAb complexes cause massive (>100-fold) expansion of CD8+ cells in vivo, whereas others selectively stimulate CD4+ T regs. Thus, different cytokine-antibody complexes can be used to selectively boost or inhibit the immune response. 相似文献
9.
CTLA-4 control over Foxp3+ regulatory T cell function 总被引：1，自引：0，他引：1
Wing K Onishi Y Prieto-Martin P Yamaguchi T Miyara M Fehervari Z Nomura T Sakaguchi S 《Science (New York, N.Y.)》2008,322(5899):271-275
Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs-in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells. 相似文献
10.
Engraftment and development of human T and B cells in mice after bone marrow transplantation. 总被引：9，自引：0，他引：9
I Lubin Y Faktorowich T Lapidot Y Gan Z Eshhar E Gazit M Levite Y Reisner 《Science (New York, N.Y.)》1991,252(5004):427-431
A model for human lymphocyte ontogeny has been developed in a normal mouse. Human bone marrow, depleted of mature T and B lymphocytes, and bone marrow from mice with severe combined immunodeficiency were transplanted into lethally irradiated BALB/c mice. Human B and T cells were first detected 2 to 4 months after transplantation and persisted for at least 6 months. Most human thymocytes (30 to 50 percent of total thymocytes) were CD3+CD4+CD8+. Human immunoglobulin was detected in some chimeras, and a human antibody response to dinitrophenol could be generated after primary and secondary immunization. 相似文献
11.
Anderson AC Anderson DE Bregoli L Hastings WD Kassam N Lei C Chandwaskar R Karman J Su EW Hirashima M Bruce JN Kane LP Kuchroo VK Hafler DA 《Science (New York, N.Y.)》2007,318(5853):1141-1143
CD4+ T helper 1 (TH1) cells are important mediators of inflammation and are regulated by numerous pathways, including the negative immune receptor Tim-3. We found that Tim-3 is constitutively expressed on cells of the innate immune system in both mice and humans, and that it can synergize with Toll-like receptors. Moreover, an antibody agonist of Tim-3 acted as an adjuvant during induced immune responses, and Tim-3 ligation induced distinct signaling events in T cells and dendritic cells; the latter finding could explain the apparent divergent functions of Tim-3 in these cell types. Thus, by virtue of differential expression on innate versus adaptive immune cells, Tim-3 can either promote or terminate TH1 immunity and may be able to influence a range of inflammatory conditions. 相似文献
12.
Peng G Guo Z Kiniwa Y Voo KS Peng W Fu T Wang DY Li Y Wang HY Wang RF 《Science (New York, N.Y.)》2005,309(5739):1380-1384
CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases. 相似文献
13.
The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development. 相似文献
14.
15.
Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells 总被引：1，自引：0，他引：1
Intestinal intraepithelial T lymphocytes (IELs) are likely to play a key role in host mucosal immunity and, unlike other T cells, have been proposed to differentiate from local precursors rather than from thymocytes. We show here that IELs expressing the alphabeta T cell receptor are derived from precursors that express RORgammat, an orphan nuclear hormone receptor detected only in immature CD4+CD8+ thymocytes, fetal lymphoid tissue-inducer (LTi) cells, and LTi-like cells in cryptopatches within the adult intestinal lamina propria. Using cell fate mapping, we found that all intestinal alphabeta T cells are progeny of CD4+CD8+ thymocytes, indicating that the adult intestine is not a significant site for alphabeta T cell development. Our results suggest that intestinal RORgammat+ cells are local organizers of mucosal lymphoid tissue. 相似文献
16.
Human immunodeficiency virus infection of human-PBL-SCID mice 总被引：32，自引：0，他引：32
D E Mosier R J Gulizia S M Baird D B Wilson D H Spector S A Spector 《Science (New York, N.Y.)》1991,251(4995):791-794
Severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (hu-PBL-SCID mice) have inducible human immune function and may be useful as a small animal model for acquired immunodeficiency syndrome (AIDS) research. Hu-PBL-SCID mice infected with human immunodeficiency virus-1 (HIV-1) contained virus that was recoverable by culture from the peritoneal cavity, spleen, peripheral blood, and lymph nodes for up to 16 weeks after infection; viral sequences were also detected by in situ hybridization and by amplification with the polymerase chain reaction (PCR). Mice could be infected with multiple strains of HIV-1, including LAV-1/Bru, IIIB, MN, SF2, and SF13. HIV-1 infection affected the concentration of human immunoglobulin and the number of CD4+ T cells in the mice. These results support the use of the hu-PBL-SCID mouse for studies of the pathogenesis and treatment of AIDS. 相似文献
17.
【目的】提高猪繁殖与呼吸综合征病毒（PRRSV）基因免疫的效果,构建含CpG基序和PRRSV ORF5的真核重组表达质粒CpG-pVAX1-ORF5。【方法】经酶切鉴定和序列测定,将重组质粒转染COS-7细胞,经间接免疫荧光试验证实CpG-pVAX1-ORF5可表达PRRSV GP5蛋白。免疫SPF小鼠,检测鼠的特异性抗体滴度、脾T淋巴细胞亚群数量（CD4+和CD8+）以及淋巴细胞增殖反应（MTT法）水平。【结果】本试验构建的含CpG基序真核重组表达质粒CpG-pVAX1-ORF5能诱导小鼠产生针对PRRSV的体液免疫与细胞免疫。【结论】CpG-ODN可提高PRRSV基因疫苗的免疫效果。 相似文献
18.
研究了具有潜伏细胞和CTL免疫反应的HIV动力学模型.利用Lyapunov函数法分析了系统的全局稳定性. 相似文献
19.
Much progress has been made in understanding how the immune system is regulated, with a great deal of recent interest in naturally occurring CD4+ regulatory T cells that actively engage in the maintenance of immunological self-tolerance and immune homeostasis. The challenge ahead for immunologists is the further elucidation of the molecular and cellular processes that govern the development and function of these cells. From this, exciting possibilities are emerging for the manipulation of regulatory T cell pathways in treating immunological diseases and suppressing or augmenting physiological immune responses. 相似文献
20.
Expanded HIV-1 cellular tropism by phenotypic mixing with murine endogenous retroviruses 总被引：26，自引：0，他引：26
P Lusso F di Marzo Veronese B Ensoli G Franchini C Jemma S E DeRocco V S Kalyanaraman R C Gallo 《Science (New York, N.Y.)》1990,247(4944):848-852
In view of the current interest in in vivo murine models for acquired immunodeficiency syndrome (AIDS), the interaction between human immunodeficiency virus type 1 (HIV-1) and endogenous murine leukemia virus (MuLV)-related retroviruses was investigated with a human leukemic T cell line (PF-382x) that acquired xenotropic MuLV (X-MuLV) after in vivo passage in immunosuppressed mice. Despite similar levels of membrane CD4 expression and HIV-1 125I-labeled gp 120 binding, a dramatic acceleration in the time course of HIV-1 infection was observed in PF-382x compared to its X-MuLV-negative counterpart (PF-382). Moreover, PF-382 cells coinfected by X-MuLV and HIV-1 generated a progeny of phenotypically mixed viral particles, enabling HIV-1 to productively infect a panel of CD4- human cells, including B lymphoid cells and purified normal peripheral blood CD4-/CD8+ T lymphocytes. Mixed viral phenotypes were also produced by human CD4+ T cells coinfected with an amphotropic MuLV-related retrovirus (A-MuLV) and HIV-1. These data show that endogenous MuLV acquired by human cells transplanted into mice can significantly interact with HIV-1, thereby inducing important alterations of HIV-1 biological properties. 相似文献