scholarly journals Prevention of Peripheral Tolerance by a Dendritic Cell Growth Factor: Flt3 Ligand as an Adjuvant

1998 ◽  
Vol 188 (11) ◽  
pp. 2075-2082 ◽  
Author(s):  
Bali Pulendran ◽  
J.L. Smith ◽  
M. Jenkins ◽  
M. Schoenborn ◽  
E. Maraskovsky ◽  
...  
Keyword(s):  
Tolerance Induction ◽  
Cd40 Ligand ◽  
Peripheral Tolerance ◽  
Clinical Settings ◽  
Flt3 Ligand ◽  
Systemic Injection ◽  
Large Numbers ◽  
Factor Α ◽  
Antigen Presenting

Injections of soluble proteins are poorly immunogenic, and often elicit antigen-specific tolerance. The mechanism of this phenomenon has been an enduring puzzle, but it has been speculated that tolerance induction may be due to antigen presentation by poorly stimulatory, resting B cells, which lack specific immunoglobulin receptors for the protein. In contrast, adjuvants, or infectious agents, which cause the release of proinflammatory cytokines such as tumor necrosis factor α and interleukin 1β in vivo are believed to recruit and activate professional antigen-presenting cells to the site(s) of infection, thereby eliciting immunity. Here we show that administration of Flt3 ligand (FL), a cytokine capable of inducing large numbers of dendritic cells (DCs) in vivo, (a) dramatically enhances the sensitivity of antigen-specific B and T cell responses to systemic injection of a soluble protein, through a CD40–CD40 ligand–dependent mechanism; (b) influences the class of antibody produced; and (c) enables productive immune responses to otherwise tolerogenic protocols. These data support the hypothesis that the delicate balance between immunity and tolerance in vivo is pivotally controlled by DCs, and underscore the potential of FL as a vaccine adjuvant for immunotherapy in infectious disease and other clinical settings.

scholarly journals CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells

2002 ◽  
Vol 197 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Melanie S. Vacchio ◽  
Richard J. Hodes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
Cd8 Cells ◽  
Costimulatory Signal ◽  
Cd28 Costimulation

Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y–specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y–specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells.

Functional domains of HSP70 stimulate generation of cytokines and chemokines, maturation of dendritic cells and adjuvanticity

2004 ◽  
Vol 32 (4) ◽  
pp. 629-632 ◽  
Author(s):  
T. Lehner ◽  
Y. Wang ◽  
T. Whittall ◽  
E. McGowan ◽  
C.G. Kelly ◽  
...  
Keyword(s):  
Amino Acids ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cd40 Ligand ◽  
Interleukin 12 ◽  
Cytokines And Chemokines ◽  
Cc Chemokines ◽  
Factor Α ◽  
Antigen Presenting ◽  
Necrosis Factor

Microbial HSP70 (heat-shock protein 70) consists of three functionally distinct domains: an N-terminal 44 kDa ATPase portion (amino acids 1–358), followed by an 18 kDa peptide-binding domain (amino acids 359–494) and a C-terminal 10 kDa fragment (amino acids 495–609). Immunological functions of these three different domains in stimulating monocytes and dendritic cells have not been fully defined. However, the C-terminal portion (amino acids 359–610) stimulates the production of CC chemokines, IL-12 (interleukin-12), TNFα(tumour necrosis factor α), NO and maturation of dendritic cells and also functions as an adjuvant in the induction of immune responses. In contrast, the ATPase domain of microbial HSP70 mostly lacks these functions. Since the receptor for HSP70 is CD40, which with its CD40 ligand constitutes a major co-stimulatory pathway in the interaction between antigen-presenting cells and T-cells, HSP70 may function as an alternative ligand to CD40L. HSP70–CD40 interaction has been demonstrated in non-human primates to play a role in HIV infection, in protection against Mycobacterium tuberculosis and in conversion of tolerance to immunity.

scholarly journals FLT3-Ligand Treatment of Humanized Mice Results in the Generation of Large Numbers of CD141+and CD1c+Dendritic Cells In Vivo

2014 ◽  
Vol 192 (4) ◽  
pp. 1982-1989 ◽  
Author(s):  
Yitian Ding ◽  
Andrew Wilkinson ◽  
Adi Idris ◽  
Ben Fancke ◽  
Meredith O’Keeffe ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Humanized Mice ◽  
Flt3 Ligand ◽  
Large Numbers

The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4300-4306 ◽  
Author(s):  
Patrizia Rovere ◽  
Giuseppe Peri ◽  
Fausto Fazzini ◽  
Barbara Bottazzi ◽  
Andrea Doni ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Acute Phase Proteins ◽  
Inflammatory Reactions ◽  
Reactive Protein ◽  
Factor Α ◽  
Antigen Presenting ◽  
Dying Cells

Pentraxins are acute-phase proteins produced in vivo during inflammatory reactions. Classical short pentraxins, C-reactive protein, and serum amyloid P component are generated in the liver in response to interleukin (IL)–6. The long pentraxin PTX3 is produced in tissues under the control of primary proinflammatory signals, such as lipopolysaccharide, IL-1β, and tumor necrosis factor-α, which also promote maturation of dendritic cells (DCs). Cell death commonly occurs during inflammatory reactions. In this study, it is shown that PTX3 specifically binds to dying cells. The binding was dose dependent and saturable. Recognition was restricted to extranuclear membrane domains and to a chronological window after UV irradiation or after CD95 cross-linking–induced or spontaneous cell death in vitro. PTX3 bound to necrotic cells to a lesser extent. Human DCs failed to internalize dying cells in the presence of PTX3, while they took up normally soluble or inert particulate substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues.

Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo

Immunity ◽  
1994 ◽  
Vol 1 (4) ◽  
pp. 327-339 ◽  
Author(s):  
Elizabeth R. Kearney ◽  
Kathryn A. Pape ◽  
Dennis Y. Loh ◽  
Marc K. Jenkins
Keyword(s):  
T Cell ◽  
Tolerance Induction ◽  
Peripheral Tolerance ◽  
T Cell Immunity ◽  
Cell Immunity

scholarly journals Persistence of Peptide-induced CD4+ T cell Anergy In Vitro

1998 ◽  
Vol 187 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Kelli R. Ryan ◽  
Brian D. Evavold
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Tolerance ◽  
Single Amino Acid ◽  
Peptide Analog ◽  
Cell Responses ◽  
T Cell Anergy ◽  
Antigen Presenting

Clonal T cell unresponsiveness, or anergy, has been proposed as a mechanism of peripheral tolerance in vivo, and as a potential means of curbing unwanted T cell responses. In this study, anergy was induced in a T helper cell (Th) clone reactive to hemoglobin (Hb) peptide 64–76 by coculture of the T cells with live antigen-presenting cells (APCs) and 74L, a peptide analog of Hb(64–76) that contains a single amino acid substitution of leucine for glycine at position 74, or with a low concentration of the agonist ligand. The anergic state was characterized by blunted proliferation and interleukin (IL) 2 production upon restimulation with Hb(64–76), and was not the result of impaired TCR/CD3 downmodulation. The addition of exogenous IL-12 transiently restored proliferation of the anergic lines, but removal of IL-12 from culture returned the T cells to their nonproliferative state. Interestingly, persistence of the anergic phenotype was observed despite biweekly restimulation with antigen, APCs, and IL-2. Thus, T cell unresponsiveness induced by a peptide produced a stable, persistent anergic state in a Th0 clone that was not reversible by stimulation with IL-2 or -12.

The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4300-4306 ◽  
Author(s):  
Patrizia Rovere ◽  
Giuseppe Peri ◽  
Fausto Fazzini ◽  
Barbara Bottazzi ◽  
Andrea Doni ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Acute Phase Proteins ◽  
Inflammatory Reactions ◽  
Reactive Protein ◽  
Factor Α ◽  
Antigen Presenting ◽  
Dying Cells

Abstract Pentraxins are acute-phase proteins produced in vivo during inflammatory reactions. Classical short pentraxins, C-reactive protein, and serum amyloid P component are generated in the liver in response to interleukin (IL)–6. The long pentraxin PTX3 is produced in tissues under the control of primary proinflammatory signals, such as lipopolysaccharide, IL-1β, and tumor necrosis factor-α, which also promote maturation of dendritic cells (DCs). Cell death commonly occurs during inflammatory reactions. In this study, it is shown that PTX3 specifically binds to dying cells. The binding was dose dependent and saturable. Recognition was restricted to extranuclear membrane domains and to a chronological window after UV irradiation or after CD95 cross-linking–induced or spontaneous cell death in vitro. PTX3 bound to necrotic cells to a lesser extent. Human DCs failed to internalize dying cells in the presence of PTX3, while they took up normally soluble or inert particulate substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues.

HIV-1-infected dendritic cells up-regulate cell surface markers but fail to produce IL-12 p70 in response to CD40 ligand stimulation

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2810-2817 ◽  
Author(s):  
Anna Smed-Sörensen ◽  
Karin Loré ◽  
Lilian Walther-Jallow ◽  
Jan Andersson ◽  
Anna-Lena Spetz
Keyword(s):  
Dendritic Cells ◽  
Cd40 Ligand ◽  
Interleukin 12 ◽  
Ligand Stimulation ◽  
Effector Cytokines ◽  
Factor Α ◽  
Antigen Presenting ◽  
Hiv 1 ◽  
Necrosis Factor

Abstract Dendritic cells (DCs) are antigen-presenting cells with the capacity to prime naive T cells for efficient cellular responses against pathogens such as HIV-1. DCs are also susceptible to HIV-1 infection, which may impair their ability to induce immunity. Here, we examined the ability of HIV-1-infected, in vitro-derived DCs to respond to CD40 ligand (CD40L) stimulation with the aim to study events during early HIV-1 infection. HIV-1BaL-infected p24+ DCs were detected after only 3 days of exposure to highly concentrated virus. We show that HIV-1-infected DCs up-regulated costimulatory molecules, but were skewed in their production of effector cytokines in response to CD40L stimulation. CD40L stimulation induced significant secretion of tumor necrosis factor α (TNFα) and interleukin 12 (IL-12) p70 from both HIV-1-exposed and unexposed DCs. Intracellular stainings of HIV-1-exposed DCs revealed that TNFα could be detected in both the p24- and p24+ DCs, but IL-12 p70 could be found only in the p24- DCs. Thus, although p24+ DCs showed a mature phenotype similar to p24- DCs after CD40L stimulation, they appeared to have an impaired cytokine profile. These observations suggest that HIV-1 infection disables DC function, a phenomenon that may be relevant for optimal induction of HIV-1-specific immune responses. (Blood. 2004;104:2810-2817)

Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine production

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2733-2743 ◽  
Author(s):  
Neil C. Robson ◽  
David J. Phillips ◽  
Tristan McAlpine ◽  
Amanda Shin ◽  
Suzanne Svobodova ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Human Monocyte ◽  
Transforming Growth Factor Β ◽  
Cd40 Ligand ◽  
Activin A ◽  
Type I ◽  
Chemokine Production ◽  
Specific Effector ◽  
Factor Α

Activin-A is a transforming growth factor-β (TGF-β) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c+ and CD123+ peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c+ myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-α [TNF-α]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8+ T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity.

scholarly journals Cd40 Ligand (Cd154) Triggers a Short-Term Cd4+ T Cell Activation Response That Results in Secretion of Immunomodulatory Cytokines and Apoptosis

2000 ◽  
Vol 191 (4) ◽  
pp. 651-660 ◽  
Author(s):  
Patrick J. Blair ◽  
James L. Riley ◽  
David M. Harlan ◽  
Ryo Abe ◽  
Douglas K. Tadaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd40 Ligand ◽  
Interferon Γ ◽  
Antiapoptotic Proteins ◽  
Enhanced Production ◽  
Factor Α

Signals generated through CD28–B7 and CD40 ligand (CD40L)–CD40 interactions have been shown to be crucial for the induction of long-term allograft survivability. We have recently demonstrated that humanized anti-CD40L (hu5C8) prevents rejection of mismatched renal allografts in primates. To investigate potential mechanisms of CD40L–induced allograft acceptance, we coimmobilized hu5C8 with suboptimal amounts of anti-CD3 to stimulate CD4+ T cells. We now report that anti-CD3/CD40L costimulation results in CD28-independent activation and subsequent deletion of resting T cells. Coligation of CD3 and CD40L increased expression of CD69, CD25, and CD54 on CD4+ T cells. We also found that costimulation with anti-CD3/CD40L resulted in enhanced production of interleukin (IL)-10, interferon γ, and tumor necrosis factor α but not IL-2 or IL-6. Interestingly, after several days, anti-CD3/CD40L–mediated activation was followed by apoptosis in a significant population of cells. Consistent with that observation, anti-CD3/CD40L did not enhance the antiapoptotic proteins Bcl-2 and Bcl-xL. Further, the addition of CD28 at 24 h failed to rescue those cells induced to die after costimulation with anti-CD3/CD40L. Together, these data suggest that the graft-sparing effect of hu5C8 in vivo may result in part from early and direct effects on CD4+ T cells, including a vigorous induction of immunomodulatory cytokines and/or apoptosis of allograft-specific T cells.

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