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1.
To help design needed new vaccines for pneumonic plague, we targeted the Yersinia pestis LcrV protein directly to CD8α + DEC‐205 + or CD8α ? DCIR2 + DC along with a clinically feasible adjuvant, poly IC. By studying Y. pestis in mice, we could evaluate the capacity of this targeting approach to protect against a human pathogen. The DEC‐targeted LcrV induced polarized Th1 immunity, whereas DCIR2‐targeted LcrV induced fewer CD4 + T cells secreting IFN‐γ, but higher IL‐4, IL‐5, IL‐10, and IL‐13 production. DCIR‐2 targeting elicited higher anti‐LcrV Ab titers than DEC targeting, which were comparable to a protein vaccine given in alhydrogel adjuvant, but the latter did not induce detectable T‐cell immunity. When DEC‐ and DCIR2‐targeted and F1‐V+ alhydrogel‐vaccinated mice were challenged 6 wk after vaccination with the virulent CO92 Y. pestis, the protection level and Ab titers induced by DCIR2 targeting were similar to those induced by F1‐V protein with alhydrogel vaccination. Therefore, LcrV targeting to DC elicits combined humoral and cellular immunity, and for the first time with this approach, also induces protection in a mouse model for a human pathogen. 相似文献
2.
CD4 + T follicular helper (T FH) cells are central for generation of long‐term B‐cell immunity. A defining phenotypic attribute of T FH cells is the expression of the chemokine R CXCR5, and T FH cells are typically identified by co‐expression of CXCR5 together with other markers such as PD‐1, ICOS, and Bcl‐6. Herein, we report high‐level expression of the nutrient transporter folate R 4 (FR4) on T FH cells in acute viral infection. Distinct from the expression profile of conventional T FH markers, FR4 was highly expressed by naive CD4 + T cells, was downregulated after activation and subsequently re‐expressed on T FH cells. Furthermore, FR4 expression was maintained, albeit at lower levels, on memory T FH cells. Comparative gene expression profiling of FR4 hi versus FR4 lo Ag‐specific CD4 + effector T cells revealed a molecular signature consistent with T FH and T H1 subsets, respectively. Interestingly, genes involved in the purine metabolic pathway, including the ecto‐enzyme CD73, were enriched in T FH cells compared with T H1 cells, and phenotypic analysis confirmed expression of CD73 on T FH cells. As there is now considerable interest in developing vaccines that would induce optimal T FH cell responses, the identification of two novel cell surface markers should be useful in characterization and identification of T FH cells following vaccination and infection. 相似文献
3.
T follicular helper (T FH) cells play an essential role in promoting B cell responses and antibody affinity maturation in germinal centers (GC). A subset of memory CD4 + T cells expressing the chemokine receptor CXCR5 has been described in human blood as phenotypically and clonally related to GC T FH cells. However, the antigen specificity and relationship of these circulating T FH (cT FH) cells with other memory CD4 + T cells remain poorly defined. Combining antigenic stimulation and T cell receptor (TCR) Vβ sequencing, we found T cells specific to tetanus toxoid (TT), influenza vaccine (Flu), or Candida albicans ( C.alb) in both cT FH and non-cT FH subsets, although with different frequencies and effector functions. Interestingly, cT FH and non-cT FH cells specific for C.alb or TT had a largely overlapping TCR Vβ repertoire while the repertoire of Flu-specific cT FH and non-cT FH cells was distinct. Furthermore, Flu-specific but not C.alb-specific PD-1 + cT FH cells had a “GC T FH-like” phenotype, with overexpression of IL21, CXCL13, and BCL6. Longitudinal analysis of serial blood donations showed that Flu-specific cT FH and non-cT FH cells persisted as stable repertoires for years. Collectively, our study provides insights on the relationship of cT FH with non-cT FH cells and on the heterogeneity and persistence of antigen-specific human cT FH cells. 相似文献
4.
Evidence is accumulating to suggest the existence of polarized human T-cell responses, reminiscent of T H1 and T H2 subsets described for mouse T cells. Human T H1 cells preferentially develop during infections by intracellular bacteria and trigger phagocyte-mediated host defense, whereas T H2 cells, which predominate during helminthic infestations and in response to common environmental allergens, are responsible for phagocyte-independent host response. Human T H1 and T H2 cells exhibit not only different functional properties but probably also distinct surface markers; T H2, but not T H1, clones express membrane CD30 and release the soluble form of CD30, a member of the TNF receptor superfamily. The cytokine profile of natural immunity evoked by different offending agents in the context of different host genetic backgrounds appears to be the most critical factor in determining the phenotype of the subsequent specific response. IL-12 and IFN- and produced by macrophages and NK cells favor the development of T H1 cells, whereas the early production of IL-4 by a stillunidentified cell type favors the development of T H2 cells. Clearly, polarized human T H1 and T H2 responses not only play different roles in protection, they can also promote different immunopathological reactions. Strong and persistent T H1 responses seen to be involved in organ-specific autoimmunity, contact dermatitis, and some chronic inflammatory disorders of unknown etiology. In contrast, polarized T H2 responses favor a reduced protection against the majority of infectious agents (including HIV) and, in genetically predisposed hosts, are responsible for triggering of allergic atopic disorders. 相似文献
6.
The secondary humoral immune response is characterized by plasma B cells secreting isotype‐switched and affinity‐matured antibodies. The efficient generation of plasma B cells in the GC depends on the presence of follicular helper T (T FH) cells, a cell type thought to arise from naive CD4‐positive T cells by a hitherto unresolved differentiation pathway. Mice deficient for CD155, an adhesion receptor of the immunoglobulin superfamily, are impaired to mount a secondary humoral immune response upon oral administration of antigen, while the primary IgM response is unaffected. Here, we show that mice lacking CD155 harbor significantly reduced numbers of T FH cells in their Peyer's patches. This was paralleled by a decreased frequency of T FH cells in the GC. Moreover, the CD155 ligand CD226, which is involved in T‐cell activation, is down‐regulated during T FH cell differentiation, resulting in a complete absence of CD226 on those T FH cells residing in the GC. Concurrently, the expression of TIGIT/WUCAM, a newly discovered CD155 ligand, is induced in T FH cells. Thus, these cells replace an activating by a putative inhibitory CD155‐binding partner during their differentiation. 相似文献
7.
Allergic diseases are characterized by overactive type 2 immune responses to allergens and immunoglobulin E (IgE)-mediated hypersensitivity. Emerging evidence suggests that follicular helper T (T FH) cells, rather than type 2 T-helper (T H2) cells, play a crucial role in controlling IgE production. However, follicular regulatory T (T FR) cells, a specialized subset of regulatory T (T REG) cells resident in B-cell follicles, restricts T FH cell-mediated help in extrafollicular antibody production, germinal center (GC) formation, immunoglobulin affinity maturation, and long-lived, high-affinity plasma and memory B-cell differentiation. In mouse models of allergic asthma and food allergy, CXCR5 + T FH cells, not CXCR5 − conventional T H2 cells, are needed to support IgE production, otherwise exacerbated by CXCR5 + T FR cell deletion. Upregulation of T FH cell activities, including a skewing toward type 2 T FH (T FH2) and IL-13 producing T FH (T FH13) phenotypes, and defects in T FR cells have been identified in patients with allergic diseases. Allergen immunotherapy (AIT) reinstates the balance between T FH and T FR cells in patients with allergic diseases, resulting in clinical benefits. Collectively, further understanding of T FH and T FR cells and their role in the immunopathogenesis of allergic diseases creates opportunities to develop novel therapeutic approaches. 相似文献
8.
Follicular helper T (T FH) cells are essential for inducing germinal centre (GC) reactions to mediate humoral adaptive immunity and antiviral effects, but the mechanisms of T FH cell differentiation remain unclear. Here, we found that the hippo kinase MST1 is critical for T FH cell differentiation, GC formation, and antibody production under steady-state conditions and viral infection. MST1 deficiency intrinsically enhanced T FH cell differentiation and GC reactions in vivo and in vitro. Mechanistically, mTOR and HIF1α signalling is involved in glucose metabolism and increased glycolysis and decreased OXPHOS, which are critically required for MST1 deficiency-directed T FH cell differentiation. Moreover, upregulated Foxo3 expression is critically responsible for T FH cell differentiation induced by Mst1−/−. Thus, our findings identify a previously unrecognized relationship between hippo kinase MST1 signalling and mTOR-HIF1α-metabolic reprogramming coupled with Foxo3 signalling in reprogramming T FH cell differentiation. 相似文献
9.
Follicular T‐helper (T FH) cells play a crucial role in three aspects of the germinal center (GC) response. They promote GC formation, arbitrate competition among GC B cells to determine the outcome of affinity maturation, and regulate GC output of memory and plasma cells to shape the long‐lived humoral immune memory. Of fundamental importance are dynamic physical interactions between T FH and B cells, which are the main platform for T FH cells to deliver “help” factors to B cells and also for reciprocal signaling from B cells to maintain the helper state of T FH cells. Recent work has significantly expanded our understanding of how T‐B interactions are spatiotemporally regulated and molecularly orchestrated to fulfill those T FH functions. In this review, we elaborate two modes of T‐B interactions, the antigen‐specific or cognate mode in which T FH cells engage individual antigen‐presenting B cells and the antigen nonspecific bystander mode in which T FH cells are engaged with the ensemble of follicular B cells. We discuss findings that indicate how short‐lived cognate T‐B contacts coupled with an intercellular positive feedback drive affinity‐based selection and how bystander interactions between T and B cells regulate follicular T‐cell recruitment and maintenance of an appropriate helper state. We argue that this combination of bystander and cognate interactions with B cells constantly shapes the internal state of T FH cells and provides the platform to execute their helper functions. 相似文献
10.
Autoimmunity against the Goodpasture antigen α3IV‐NC1 results in crescentic glomerulonephritis (GN). Both antibodies and T cells directed against α3IV‐NC1 have been implicated in disease development and progression. Using the model of experimental autoimmune glomerulonephritis (EAG) in DBA/1 mice, we aimed to characterize the frequency and function of α3IV‐NC1‐specific CD4 + T cells in the kidneys. DBA/1 mice repeatedly immunized with human α3IV‐NC1 developed necrotizing/crescentic GN. Kidneys with crescentic GN contained CD4 + cells responding to α3IV‐NC1 with the production of IFN‐γ or IL‐17A, demonstrating the accumulation of both α3IV‐NC1‐specific T H1 and T H17 cells. To test the functional relevance of T H1 and T H17 cells, EAG was induced in DBA/1 mice deficient in IFN‐γR, IL‐17A or IL‐23p19. Mice of all knockout groups mounted α3IV‐NC1 IgG, developed nephrotic range proteinuria, and IgG deposition to the glomerular basement membranes at levels similar to immunized wild‐type mice. However, all knockout groups showed significantly fewer glomerular crescents and attenuated tubulointerstitial damage. Our results suggest that both α3IV‐NC1‐specific T H1 and T H17 cells accumulate in the kidneys and are crucial for the development of necrotizing/crescentic GN. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 相似文献
11.
DEC205/CD205, an endocytic receptor of C-type multilectin, is expressed highly in dendritic cells (DCs). DEC205 was shown to efficiently deliver vaccine antigens in surrogate ligands to the antigen processing and presentation machinery of DCs, which resulted in the development of DC-targeted vaccines employing anti-DC monoclonal antibodies (mAbs). During our studies to characterize a variety of anti-DC mAbs including anti-DEC205 by flow cytometric analysis, we discovered that a secondary anti-immunoglobulin antibody conjugated with PE-Cy5.5 bound strongly to the cells expressing mouse DEC205 (mDEC205) without incubation of a primary anti-mDEC205 mAb. In the present study we demonstrate that various antibodies and streptavidin conjugated with PE-Cy5.5 bind to the mDEC205-expressing cells including CHO, KIT6, and HEK293 cells. The interaction between the PE-Cy5.5 conjugates and the cells expressing mDEC205 appears distinctive, since none of the PE-Cy5.5 conjugates bind to the cells that express human DEC205 on surface. Besides, only PE-Cy5.5 conjugates bind strongly to mDEC205-expressing cells; PerCP-Cy5.5, APC-Cy5.5, and Cy5.5 conjugates bind weakly; PE, PE-Cy5, Cy5, FITC, or Alexa488 conjugates do not bind to mDEC205-expressing cells. Therefore the use of PE-Cy5.5 conjugates, widely utilized in multicolor flow cytometry, requires precaution against nonspecific binding to mDEC205-positive cells. 相似文献
12.
Selective IgM deficiency (SIgMD) is a rare immunodeficiency characterized by serum IgM below two standard of mean, and normal IgG and IgA levels. Both in human and mice with selective IgM deficiency, germinal centers cells are decreased. The development of germinal center and humoral immunity are regulated in part by follicular helper T (T FH) and follicular regulatory T (T FR) cells. However, the analysis of circulating T FH (cT FH) and T FR (cT FR) cells in the pathogenesis of SIgMD has not been explored. We observed lower percentage of cT FR cells in SIgMD patients than in control group. However, we did not observe any significant difference in the percentage of cT FH cells and their subsets between both experimental groups. When data were analyzed according to specific antibody response to pneumococcal polysaccharide, we observed a higher percentage of cT FH cells in SIgMD patients with specific antibody deficiency than in SIgMD patients with normal specific antibody response. Our results suggest that cT FH cells and their subsets are preserved in SIgMD patients. However, the role of lower percentage of cT FR cells in the pathogenesis of this immunodeficiency is not clear. 相似文献
13.
Autoimmune regulator (Aire), primarily expressed in medullary thymic epithelial cells (mTECs), maintains central immune tolerance through the clearance of self-reactive T cells. Aire can also be expressed in dendritic cells (DCs), and DCs can mediate T follicular helper (T FH) cell differentiation and self-reactive B cell activation through inducible costimulator molecule ligand (ICOSL) and interleukin 6 (IL-6), which can cause autoimmune diseases. To confirm whether Aire in DCs affects T FH cell differentiation and to determine the role of Aire in the maintenance of peripheral immune tolerance, this study observed the effects of Aire deficiency on T FH cells using Aire knockout mice. The results showed that Aire deficiency caused increased number of T FH cells, both in vivo and in vitro. Further studies showed that Aire deficiency promoted T FH differentiation through the upregulation of ICOSL and IL-6 in DCs. Thus Aire could suppress the expression of ICOSL and IL-6 to inhibit T FH cell differentiation. 相似文献
14.
Dendritic cells (DCs) are a complex network of specialised antigen-presenting cells that are critical initiators of adaptive immunity. Targeting antigen directly to DCs in situ is a vaccination strategy that selectively delivers antigen to receptors expressed by DC subtypes. This approach exploits specific DC subset functions of antigen uptake and presentation. Here, we review DC-targeted vaccination strategies that are designed to elicit effective cross-presentation for CD8 + T cell immunity. In particular, we focus on approaches that exploit receptors highly expressed by mouse and human cDCs equipped with superior cross-presentation capacity. These receptors include DEC205, Clec9A and XCR1. Targeting DC receptors Clec12A, Clec4A4 and mannose receptor is also reviewed. Outcomes of DC-targeted vaccination in mouse models through to human clinical trials is discussed. This is a promising new vaccination approach capable of directly targeting the cross-presentation pathway for prevention and treatment of tumours and infectious diseases. 相似文献
15.
An effective adaptive immune response relies on the ability of lymphocytes to rapidly act upon a variety of insults. In T lymphocytes, this response includes cell growth, clonal expansion, differentiation, and cytokine production, all of which place a significant energy burden on the cell. Recent evidence shows that T‐cell metabolic reprogramming is an essential component of the adaptive immune response and specific metabolic pathways dictate T‐cell fate decisions, including the development of T H17 versus T regulatory (Treg) cells. T H17 cells have garnered significant attention due to their roles in the pathology of immune‐mediated inflammatory diseases. Attempts to characterize T H17 cells have demonstrated that they are highly dynamic, adjusting their function to environmental cues, which dictate their metabolic program. In this review, we highlight recent data demonstrating the impact of cellular metabolism on the T H17/Treg balance and present factors that mediate T H17‐cell metabolism. Some examples of these include the differential impact of the mTOR signaling complexes on T‐helper‐cell differentiation, hypoxia inducible factor 1 alpha (HIF1α) promotion of glycolysis to favor T H17‐cell development, and ACC1‐dependent de novo fatty acid synthesis favoring T H17‐cell development over Treg cells. Finally, we discuss the potential therapeutic options and the implications of modulating T H17‐cell metabolism for the treatment of T H17‐mediated diseases. 相似文献
16.
Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H 2O 2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H 2O 2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia, and increased airway hyperreactivity. WT-Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naive mice. In contrast, the lungs of MCAT-Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H 2O 2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens. 相似文献
17.
The world population is undergoing a rapid expansion of older adults. Aging is associated with numerous changes that affect all organs and systems, including every component of the immune system. Immunosenescence is a multifaceted process characterized by poor response to vaccine and higher incidence of bacterial and viral infections, cancer, cardiovascular and autoimmune diseases. Immunosenescence has been associated with chronic low-grade inflammation referred to as inflammaging, whose underlying mechanisms remain incompletely elucidated, including age-related changes affecting components of the innate and adaptive immune system. T follicular helper (T FH) cells, present in lymphoid organs and in peripheral blood, are specialized in providing cognate help to B cells and are required for the production of immunoglobulins. Several subsets of T FH cells have been identified in humans and mice and modifications in T FH cell phenotype and function progressively occur with age. Dysfunctional T FH cells play a role in cancer, autoimmune and cardiovascular diseases, all conditions particularly prevalent in elderly subjects. A specialized population of Treg cells, named T follicular regulatory (T FR) cells, present in lymphoid organs and in peripheral blood, exerts opposing roles to T FH cells in regulating immunity. Indeed, changes in T FH/T FR cell ratio constitute a relevant feature of aging. Herein we discuss the cellular and molecular changes in both T FH cells and T FR cells that occur in aging and recent findings suggesting that T FH cells and/or their subsets could be involved in atherosclerosis, cancer, and autoimmunity. 相似文献
18.
Circulating T FH (cT FH) cells express CXCR5, PD-1, and, when activated, ICOS, and release IL-21. According to the production of IFN-γ, IL-4, and IL-17 and expression of FoxP3, these cells are also classified as cT FH1, cT FH2, cT FH17, and cT FR cells, respectively. This CD4 +T-cell subset is pivotal to efficient humoral immunity, and pregnancy appears to favor IgG production. Here, not only pregnancy amplified the in vivo production of anti-HBsAg IgG in HBV immunized women, but the frequency of cT FH cells was directly correlated with estradiol levels. In vitro, pregnancy-related dose of 17-β-estradiol (E2) directly increased the percentage of different cT FH subsets. While E2 and progesterone (P4) increased the proportion of differentiated T FH cells derived from naïve CD4 +T-cells, only E2 amplified the release of IL-21 in those cell cultures. In addition, E2 and P4 increased the proportion of memory B cells and plasma cells, respectively. In SEB-activated B/T FH cell co-cultures, E2, in the presence of P4, increased the production of total IgG. Finally, among the hormones, P4 was stronger in upregulating the percentage of IL-10 +T FR cells. Collectively, our findings suggested that E2 and P4 cooperate in the humoral immune response by favoring the expansion of different cT FH and B cell subsets. 相似文献
19.
Peripheral blood mononuclear cells with T FH phenotype from two asymptomatic XLP patients were studied. Normal/high numbers of CXCR5+, CD4+ T cells coexpressing PD-1 were demonstrated. Peripheral blood mononuclear cells (PBMC) from these patients responded to sub-optimal PHA/IL-2 stimulation upregulating ICOS and CD40L and increasing intracellular expression of IL-10, IL-21 and IL-4 by CD4+ T FH cells. However when compared to N, the time profile of activation and cytokine synthesis was different in XLP and N. While ICOS and CD40L expression in N decreased after 6–8 days, it continued to increase or was maintained in XLP cultures. Intracellular IL-10, IL-21 and IL-4 reached higher values in XLP than N after 8 days. Rather than the absence of T FH cells or their intrinsic inability to respond to stimuli, differences in the time profile of their response could contribute to impair their role as helpers of B lymphocytes. 相似文献
20.
It is well known that prostaglandin (PG) E2 exerts T cell suppression in vitro through elevating cAMP by its receptors, EP2 and EP4. However, such an action is rarely detected in vivo, leaving PGE2-mediated immunosuppression an enigma. Here we show that under strong TCR stimulation, PGE2 facilitates T helper-1 (TH-1) differentiation through activation of phosphatidylinositol-3-kinase (PI3K) by EP2 and EP4. The PGE2-EP4 signaling is also required for IL-23 production by activated dendritic cells (DCs), and the PGE2-EP2/EP4 signaling amplifies IL-23-mediated TH-17 cell expansion. Administration of an EP4-selective antagonist in vivo to mice subjected to experimental allergic encephalomyelitis (EAE) decreases accumulation of both TH-1 and TH-17 cells in regional lymph nodes, and suppresses the disease progression. These results suggest PGE2 promotes immune inflammation through TH-1 differentiation and TH-17 expansion and the EP4 antagonism is therapeutically useful for various immune diseases. 相似文献
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