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| T细胞发育简单化 | |||
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杜丽蕊 暨南大学 组织移植与免疫研究中心
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| T 细胞受体信号 | |||
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Wange RL, Huang Y. . The adaptive phase of the immune response begins with engagement on
CD4+ helper T cells of the T cell antigen receptor (TCR) by its ligand
a small foreign peptide bound to a cell surface protein of the class
II major histocompatability complex (peptide-MHC), expressed on an antigen
presenting cell. This engagement initiates a series of biochemical events
that can differentially signal the nave T cell to: 1) enter into a pathway
leading to generation of effector T cells, with the onset of rapid proliferation
and production of effector cytokines, 2) enter into a state of antigenic
non-responsiveness known as anergy, or 3) die by apoptosis. The type
of response elicited depends on multiple factors including the affinity
of the interaction, the duration of the interaction and the presence
or absence of various costimulatory signaling inputs, such as those
provided by the CD4 coreceptor and the CD28 costimulatory receptor.
In this review, we provide an overview of the signaling events that
are associated with the first of these outcomes T cell activation. In
order to present an overview of sufficiently broad scope, the depth
of discussion of each aspect of TCR signaling is by necessity limited,
and the reader is referred to the reviews cited throughout this text
for consideration of these events in more detail.
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| 免疫识别中的体细胞发生 |
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Niels Kaj Jerne
Antibody specificity is determined by structural v-genes that code for the amino acid sequences of the variable regions of antibody polypeptide chains. The present hypothesis proposes that the germ-cells of an animal carry a set of v-genes determining the combining sites of antibodies directed against a complete set of certain class of histocompatibility antigens of the species to which this animal belongs. The evolutionary development of this set of v-genes in phylogeny is traced back to the requirements for cell to cell recognition in all metazoa. The hypothesis leads to a distinction between two populations of antigen-sensitive cells. One population consists of cells forming antibodies against foreign antigens; these lymphocytes have arisen as mutants in clones descending from lymphocytic stem cells which expressed v-genes belonging to the subset (subset S) coding for antibody against histocompatibility antigens that the individual happens to possess. The other population consists of allograft rejecting lymphocytes that express v-genes of the remaining subset (subset A) coding for antibody against histocompatibility antigens of the species that the individual does not possess. The primary lymphoid organs are viewed as mutant-breeding organs. In these organs (e.g. in the thymus), the proliferation of lymphocytes expressing the v-genes of subset S and the subsequent suppression of the cells of these "forbidden" clones, leads to the selection of mutants cells expressing v-genes that have been modified by spontaneous random somatic mutation. This process generates self-tolerance as well as a diverse population of antigen-sensitive cells that reflects antibody diversity. The proliferation in the primary lymphoid organs of lymphocytes expressing v-genes of subset A generates the antigen-sensitive cell population that is responsible for allo-aggression.The theory explains how a functional immune system can develop through a selection pressure exerted by self-antigens, starting during a period in early ontogeny that precedes clonal selection by foreign antigens. The hypothesis provides explanations for the variability of the N-terminal regions of antibody polypeptide chains, for the dominant genetic control of specific immune responsiveness by histocompatibility alleles, for the relative preponderance of antigen-sensitive cells directed against allogeneic histocompatibility antigens, for antibody-idiotypes, for allelic exclusion, for the precommitment of any given antigen-sensitive lymphocyte to form antibodies of only one molecular species and for the cellular dynamics in the primary lymphoid tissues.
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CD91在递呈gp96分子伴侣肽中的作用 |
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Heat shock proteins (HSPs) such as gp96 are released from cells as a result of necrotic cell death. The ability of endogenous HSP–peptide complexes to elicit antigen-specific T cells requires representation of the chaperoned peptides by antigen-presenting cells. Re-presentation requires the uptake of HSP–peptide complexes through a receptor, suggested to be the low-density lipoprotein receptor-related protein or CD91. We have used short interfering RNA for CD91 to show that, as antigen-presenting cells lose expression of CD91, their re-presenting ability undergoes a corresponding and dramatic decline. Furthermore, as the cells recover from extinction of CD91 expression, they regain the ability to re-present peptides. The ability of cells to bind 2 macroglobulin, a previously known CD91 ligand, or HSP gp96, and their ability to process peptides chaperoned by 2 macroglobulin, undergo identical variations. These results have been obtained from studies in vitro and from an assay that measures re-presentation in vivo. In additional studies in vivo, protective tumor immunity elicited by tumor-derived gp96–peptide complexes is shown to be abrogated by anti-CD91 antisera. These studies show that CD91 is essential for re-presentation of gp96-chaperoned peptides by MHC molecules and have an important bearing on the mechanism of immunogenicity of necrotic cells.
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| 在诱发炎症的皮肤中，趋化因子CCL21上调 | |||
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Yanina Eberhard , Susana Ortiz , Alejandro Ruiz
Lascano , Raquel Kuznitzky and Horacio M Serra
Eleven normal individuals were challenged with different chemical or physical irritants. Two patients with Allergic Contact Dermatitis (ACD) were also challenged with the relevant antigen in order to have a positive control for CCL21 expression. Macroscopic as well as microscopic responses were evaluated. We observed typical ICD responses with mostly mononuclear cells in perivascular areas, but a predominance of polymorphonuclear cells away from the inflamed blood vessels and in the epidermis at 24 hours. Immunohistochemical studies showed up-regulation of CCL21 by lymphatic endothelial cells in all the biopsies taken from ICD and ACD lesions compared to normal skin. Kinetic study at 10, 48, 96 and 168 hours after contact with a classical irritant (sodium lauryl sulphate) showed that the expression of CCL21 was increased in lymphatic vessels at 10 hours, peaked at 48 hours, and then gradually declined. There was a strong correlation between CCL21 expression and the macroscopic response (r=0.69; p=0.0008), but not between CCL21 and the number of infiltrating cells in the lesions.
These results provide new evidence for the role of CCL21 in inflammatory processes. Since the up-regulation of this chemokine was observed in ICD and ACD, it is tempting to speculate that this mechanism operates independently of the type of dermal insult, facilitating the emigration of CCR7+ cells.
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| 成人干细胞的可塑性 | |||
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Amy J. Wagers, and Irving L. Weissman
Recent years have seen much excitement over the possibility that adult mammalian stem cells may be capable of differentiating across tissue lineage boundaries, and as such may represent novel, accessible, and very versatile effectors of therapeutic tissue regeneration. Yet studies proposing such "plasticity"of adult somatic stem cells remain controversial, and in general, existing evidence suggests that in vivo such unexpected transformations are exceedingly rare and in some cases can be accounted for by equally unex- pected alternative explanations ------------ |
| 造血干细胞移植后的免疫重建 | |||
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Karl Peggs Stem cell transplantation is characterized by a subsequent
period of immune deficiency, the duration and severity of which varies
according to graft manipulation, choice of graft type (donor and source),
development of graft-versus-host disease and level of residual thymic
activity. This results in -------------
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皮下免疫通过已接触抗原的皮肤树突状细胞的迁移，诱导黏膜CTLs和保护性免疫 |
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Transcutaneous immunization (TCI), the application of vaccines on the
skin, induces robust systemic and mucosal antibodies in animal models
and in humans. The means by which mucosal immune responses to vaccine
antigens are elicited by TCI has not been well characterized. We examined
the effect of TCI with an HIV peptide vaccine on the induction of mucosal
and systemic CTL responses and protective immunity against mucosal challenge
with live virus in mice. Robust HIV-specific CTL responses in the spleen
and in the gut mucosa were detected after TCI. The responses were dependent
upon the addition of an adjuvant and resulted in protection against
mucosal challenge with recombinant vaccinia virus encoding HIV gp160.
Although it is clear that adjuvant-activated DCs migrated mainly to
draining lymph nodes, coculture with specific T cells and flow cytometry
studies with DCs isolated from Peyer’s patches after TCI suggested that
activated DCs carrying skin-derived antigen also migrated from the skin
to immune-inductive sites in gut mucosa and presented antigen directly
to resident lymphocytes. These results and previous clinical trial results
support the observation that TCI is a safe and effective strategy for
inducing strong mucosal antibody and CTL responses ------------
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| 免疫调节和诱导凋亡：咪喹莫特的抗肿瘤特性的两个方面 | |||
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M. P. Schon, M. Schon Imiquimod, the first member of the imidazoquinoline family
of immune response modifiers, has proven good clinical efficacy against
basal cell carcinomas and actinic keratoses in several independent studies.
In addition, there is recent evidence that imiquimod is also efficacious
against other tumors such as cutaneous metastases of malignant melanoma
or vascular tumors. Imiquimod exerts its antitumoral effect, at least
in part, through binding to TLR-7 and TLR-8 on dendritic cells followed
by secretion of a multitude of proinflammatory cytokines. The net result
of this proinflammatory activity is a profound tumor-directed cellular
immune response. However, recent experimental and clinical data indicate
that imiquimod also possesses considerable direct pro-apoptotic activity
against tumor cells both in vitro and in vivo. This novel mode of action
appears to be independent of membrane bound death receptors, but involves
caspase activation. Induction of apoptosis by imiquimod is, at least
in part, presumably mediated through Bcl-2-dependent release of mitochondrial
cytochrome c and subsequent activation of caspase-9. The structural
analogue, resiquimod, exhibited very limited, if any, such pro-apoptotic
activity, possibly due to its lacking ability to enter the cell. Bypassing
molecular mechanisms of apoptosis deficiency by a topical compound may
be of great utility for treating certain cutaneous tumors. -------------
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| B细胞在免疫应答中的新作用 | |||
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Kirsty Minton
The cytokine milieu is crucial for determining the outcome of an immune response after T-cell–B-cell interaction, but most studies have focused on the cytokines produced by T cells. Now, it seems that B cells might have a more active role in determining the fate of immune responses than previously thought. New research in The Journal of Immunology has shown that B cells produce a dynamic profile of cytokines depending on the strength, timing and nature of stimulation they receive. The authors set up an in vitro system for B-cell stimulation using freshly isolated human B cells, B-cell receptor (BCR)-specific antibodies to mimic crosslinking with antigen, and mouse fibroblasts stably transfected with CD40L to mimic T-cell help. In vivo experiments have shown that BCR engagement alone does not induce B-cell proliferation, whereas CD40 engagement alone induces proliferation followed by apoptosis, and engagement of both BCR and CD40 results in sustained proliferation. By altering the concentration of antibody and the ratio of CD40L+ fibroblasts to B cells, they were able to mimic these three situations in vitro, creating a model that effectively reproduces the physiological situation. In this system, B cells stimulated with BCR crosslinking alone (mimicking the absence of T-cell help) did not produce significant levels of cytokines. However, when BCR crosslinking was combined with stimulation through CD40, the B cells produced high levels of tumour necrosis factor (TNF), lymphotoxin and interleukin-6 (IL-6) in a dose-dependent manner, which would promote an ongoing immune response. Staggered dual activation (24 hours of BCR crosslinking before addition of CD40L+ fibroblasts) amplified this cytokine response. This mimics the sequence of interactions in vivo, where a B cell typically encounters antigen in the B-cell zone of a lymph node before migrating to T-cell areas to receive help from CD40L+ T cells. By contrast, stimulation through CD40 alone resulted in production of the immunosuppressive cytokine IL-10 by B cells, in the absence of TNF and lymphotoxin. CD40 is expressed constitutively by B cells, so the production of IL-10 could help to ensure that bystander T-cell help does not result in inappropriate B-cell responses in the absence of cognate antigen.
This study has shown that B-cell cytokines can both amplify desirable immune responses and inhibit inappropriate responses. The moral of the story is that T cells don't always wear the trousers! ———————— ORIGINAL RESEARCH PAPER
------------- 摘自NATURE网站
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新乡医学院网络免疫学工作室 主办 深圳晶美生物工程有限公司 协办 |
