scholarly journals Mannose receptor high, M2 dermal macrophages mediate nonhealing Leishmania major infection in a Th1 immune environment

2017 ◽  
Vol 215 (1) ◽  
pp. 357-375 ◽  
Author(s):  
Sang Hun Lee ◽  
Melanie Charmoy ◽  
Audrey Romano ◽  
Andrea Paun ◽  
Mariana M. Chaves ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Mannose Receptor ◽  
T Helper ◽  
Cutaneous Lesions ◽  
Th1 Cell ◽  
Cutaneous Infections ◽  
Genetic Deletion

The origin and functional specialization of dermal macrophages in cutaneous infections have been little studied. In this paper, we show that a strain of Leishmania major (L. major Seidman [LmSd]) that produces nonhealing cutaneous lesions in conventionally resistant C57BL/6 mice was more efficiently taken up by M2-polarized bone marrow (BM)–derived macrophages (BMDMs) in vitro and by mannose receptor (MR)hi dermal macrophages in vivo compared with a healing strain (L. major Friedlin V1). Both in steady and in T helper type 1 (Th1) cell–driven inflammatory states, the MRhi dermal macrophages showed M2 characteristics. The dermal macrophages were radio resistant and not replaced by monocytes or adult BM-derived cells during infection, but were locally maintained by IL-4 and IL-10. Notably, the favored infection of M2 BMDMs by LmSd in vitro was MR dependent, and genetic deletion of MR or selective depletion of MRhi dermal macrophages by anti–CSF-1 receptor antibody reversed the nonhealing phenotype. We conclude that embryonic-derived, MRhi dermal macrophages are permissive for parasite growth even in a strong Th1-immune environment, and the preferential infection of these cells plays a crucial role in the severity of cutaneous disease.

scholarly journals A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

scholarly journals Leishmania-Derived Trimannose Modulates the Inflammatory Response To Significantly Reduce Leishmania major-Induced Lesions

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Tara L. Grinnage-Pulley ◽  
Daniel E. K. Kabotso ◽  
Chelsea L. Rintelmann ◽  
Rajarshi Roychoudhury ◽  
Robert G. Schaut ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Parasite Load ◽  
Mannose Receptor ◽  
Lesion Size ◽  
Wild Type ◽  
Cutaneous Lesions ◽  
Content Type ◽  
Latex Beads

ABSTRACTLeishmanialipophosphoglycan (LPG) is a key virulence factor, initiating inflammation resulting in cutaneous lesions. LPG is capped by various oligosaccharides. How these glycans are recognized and how they alter the course ofLeishmaniainfection are poorly understood. Previous studies synthesized α-1,2-trimannose cap sugars on latex beads and demonstrated that C57BL/6 mice coinoculated withLeishmania majorand trimannose-coated beads produced significantly higher levels of interleukin-12p40 (IL-12p40) and other proinflammatory, type 1 cytokines than mice inoculated withL. majoralone within the first 48 h of infection. However, asL. majorinfection typically progress over weeks to months, the role of trimannose in altering disease progression over the course of infection was unknown. Wild-type mice were inoculated with either trimannose-coated or carrier (uncoated) beads, infected withL. majoralone, coinoculated with carrier beads andL. major, or coinoculated with trimannose-coated beads andL. major. Trimannose treatment ofL. major-infected mice decreased the parasite load and significantly decreased the lesion size at 14 days postinfection (p.i.) compared to results for nontreated, infected mice. Infected, trimannose-treated mice had decreased IL-12p40 and IL-10 secretion and increased interferon gamma secretion at 14 days p.i. Mannose receptor knockout (MR−/−) mice lack the ability to detect trimannose. When MR−/−mice were infected withL. majorand treated with trimannose beads, they did not have decreased lesion size.Leishmania-derived trimannose represents a novel immunomodulator that provides early type 1-skewed cytokine production to control the parasite load and alter the course of cutaneous leishmaniasis.

scholarly journals Selective Expression and Functions of Interleukin 18 Receptor on T Helper (Th) Type 1 but not Th2 Cells

1998 ◽  
Vol 188 (8) ◽  
pp. 1485-1492 ◽  
Author(s):  
Damo Xu ◽  
Woon Ling Chan ◽  
Bernard P. Leung ◽  
David Hunter ◽  
Kerstin Schulz ◽  
...  
Keyword(s):  
Th2 Cells ◽  
Interleukin 18 ◽  
T Helper ◽  
Th2 Cell ◽  
A Cell ◽  
Ifn Γ

Interleukin (IL)-18 induces interferon (IFN)-γ synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rβ2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R–derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin–T cell antigen receptor-αβ transgenic mice (D011.10). Anti–IL-18R antibody inhibited IL-18– induced IFN-γ production by Th1 clones in vitro. In vivo, anti–IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-γ and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21

2005 ◽  
Vol 6 (7) ◽  
pp. 680-688 ◽  
Author(s):  
Lisa M Minter ◽  
Danielle M Turley ◽  
Pritam Das ◽  
Hyun Mu Shin ◽  
Ila Joshi ◽  
...  
Keyword(s):  
T Helper ◽  
Helper Type

scholarly journals The injection of deaggregated gamma globulins in adult mice induces antigen-specific unresponsiveness of T helper type 1 but not type 2 lymphocytes.

1992 ◽  
Vol 175 (1) ◽  
pp. 9-14 ◽  
Author(s):  
D De Wit ◽  
M Van Mechelen ◽  
M Ryelandt ◽  
A C Figueiredo ◽  
D Abramowicz ◽  
...  
Keyword(s):  
T Cells ◽  
Tolerance Induction ◽  
T Helper ◽  
Ifn Gamma ◽  
Specific Antibody Response ◽  
Adult Mice ◽  
Helper Type

Injection of adult mice with high doses of monomeric human gamma globulins (dHGG) has been previously shown to produce a state of peripheral tolerance in both B and T cells. To gain insight into the mechanism of induction and maintenance of adult tolerance in this model, we have analyzed the pattern of lymphokines produced by control and tolerant animals in response to the tolerogen. The data presented indicate that HGG-specific, interleukin 2 (IL-2)- and interferon gamma (IFN-gamma)-producing T cells (thus referred to as T helper type 1 [Th1] cells) are rendered unresponsive after in vivo administration of soluble HGG. In contrast, antigenic stimulation of T cells isolated from tolerant adult mice leads to increased production of IL-4 in vitro. In vivo challenge of dHGG-treated adult animals with hapten-coupled HGG (p-azophenylarsonate [ARS]-HGG) induced a significant ARS-specific antibody response, suggesting that tolerance induction in this model does not completely abrogate tolerogen-specific Th activity in vivo. In agreement with the in vitro data, hapten-specific antibody response of tolerant animals is characterized by a selective deficiency in the IFN-gamma-dependent IgG2a subclass. Injection of immunogenic forms of HGG into tolerant animals also produced an IL-4-dependent increase in total serum IgE levels, indicative of an increased activity of HGG-specific Th2 cells in these animals. The finding that tolerance induction differentially affects Th subpopulations suggests that crossregulation among lymphocyte subsets may play a role in the induction and/or maintenance of acquired tolerance in adults.

scholarly journals Antigen-pulsed dendritic cells can efficiently induce an antibody response in vivo.

1992 ◽  
Vol 175 (1) ◽  
pp. 15-21 ◽  
Author(s):  
T Sornasse ◽  
V Flamand ◽  
G De Becker ◽  
H Bazin ◽  
F Tielemans ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antibody Response ◽  
Interleukin 2 ◽  
Humoral Response ◽  
T Helper ◽  
Pulsed Dc ◽  
Immunization Procedure

The aim of this study was to develop an immunization procedure avoiding external adjuvant. Data are presented showing that syngeneic dendritic cells (DC), which have been pulsed in vitro with antigen, induce a strong antibody response in mice. By contrast, antigen (Ag)-pulsed low-density B cells, although equally able to induce interleukin 2 secretion by an Ag-specific T cell hybridoma in vitro, only weakly prime the mice in vivo. Moreover, we show that the injection of Ag-pulsed DC induces the synthesis of isotypes similar to the immunoglobulin classes detected after immunization with the same Ag in complete Freund's adjuvant. Importantly, high amounts of IgG2a antibodies are produced, suggesting that T helper type 1 cells are activated. Collectively, these data indicate that DC can initiate a primary humoral response and that they may be used as physiological adjuvant in vivo.

scholarly journals Deficiency in the Transcription Factor Interferon Regulatory Factor (Irf)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells

2000 ◽  
Vol 192 (3) ◽  
pp. 325-336 ◽  
Author(s):  
Michael Lohoff ◽  
Gordon S. Duncan ◽  
David Ferrick ◽  
Hans-Willi Mittrücker ◽  
Susi Bischof ◽  
...  
Keyword(s):  
Natural Killer ◽  
Leishmania Major ◽  
Nk Cell ◽  
Regulatory Element ◽  
Cell Development ◽  
T Helper ◽  
Regulatory Factor ◽  
Th1 Cell ◽  
Helper Type

Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1–mediated transcriptional regulation of IFN-inducible genes. IRF-1−/− mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1−/− mice, IRF-2−/− mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1−/− and IRF-2−/− mice, but the underlying mechanism differs. NK (but not NK+ T) cell numbers are decreased in IRF-2−/− mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.

scholarly journals Distinct Role of Antigen-Specific T Helper Type 1 (Th1) and Th2 Cells in Tumor Eradication in Vivo

1999 ◽  
Vol 190 (5) ◽  
pp. 617-628 ◽  
Author(s):  
Takashi Nishimura ◽  
Kenji Iwakabe ◽  
Masashi Sekimoto ◽  
Yasushi Ohmi ◽  
Takashi Yahata ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Th2 Cells ◽  
T Helper ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Tumor Eradication ◽  
Th1 And Th2

The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8+ T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell–deficient RAG2−/− mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8+ cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1–dependent cell–cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.

scholarly journals Selective Expression of a Stable Cell Surface Molecule on Type 2 but Not Type 1 Helper T Cells

1998 ◽  
Vol 187 (5) ◽  
pp. 787-794 ◽  
Author(s):  
Damo Xu ◽  
Woon Ling Chan ◽  
Bernard P. Leung ◽  
Fang-ping Huang ◽  
Rachel Wheeler ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Surface ◽  
Leishmania Major ◽  
Flow Cytometric Analysis ◽  
Dependent Manner ◽  
Cell Surface Molecule ◽  
Ifn Γ

T helper cell type 1 (Th1) and 2 (Th2) are central to immune regulation. However, no stable cell surface marker capable of distinguishing and separating these two subsets of CD4+ cells has yet been found. Using differential display PCR, we have identified a gene encoding a cell membrane bound molecule, originally designated ST2L, T1, DER4, or Fit, expressed constitutively and stably on the surface of murine Th2s, but not Th1s even after stimulation with a range of immunological stimuli. Antibody against a peptide derived from ST2L strongly and stably labeled the surface of cloned Th2s but not Th1s, and Th2s but not Th1s derived from naive T cells of ovalbumin T cell receptor–α/β transgenic mice. Three-color single cell flow cytometric analysis shows that cell surface ST2L coexpressed with intracellular interleukin (IL)-4, but not with interferon (IFN)-γ. The antibody selectively lysed Th2s in vitro in a complement-dependent manner. In vivo, it enhanced Th1 responses by increasing IFN-γ production and decreasing IL-4 and IL-5 synthesis. It induced resistance to Leishmania major infection in BALB/c mice and exacerbated collagen-induced arthritis in DBA/1 mice. Thus, ST2L is a stable marker distinguishing Th2s from Th1s and is also associated with Th2 functions. Hence, it may be a target for therapeutic intervention.

scholarly journals Endogenous Interleukin 4 Is Required for Development of Protective CD4+ T Helper Type 1 Cell Responses to Candida albicans

1998 ◽  
Vol 187 (3) ◽  
pp. 307-317 ◽  
Author(s):  
Antonella Mencacci ◽  
Giuseppe Del Sero ◽  
Elio Cenci ◽  
Cristiana Fè d'Ostiani ◽  
Angela Bacci ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Early Stage ◽  
Interleukin 4 ◽  
T Helper ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Helper Type

Interleukin (IL)-4–deficient mice were used to assess susceptibility to systemic or gastrointestinal Candida albicans infections, as well as parameters of innate and elicited T helper immunity. In the early stage of systemic infection with virulent C. albicans, an unopposed interferon (IFN)-γ response renders IL-4–deficient mice more resistant than wild-type mice to infection. Yet, IL-4–deficient mice failed to efficiently control infection in the late stage and succumbed to it. Defective IFN-γ and IL-12 production, but not IL-12 responsiveness, was observed in IL-4–deficient mice that failed to mount protective T helper type 1 cell (Th1)-mediated acquired immunity in response to a live vaccine strain of the yeast or upon mucosal immunization in vivo. In vitro, IL-4 primed neutrophils for cytokine release, including IL-12. However, late treatment with exogenous IL-4, while improving the outcome of infection, potentiated CD4+ Th1 responses even in the absence of neutrophils. These findings indicate that endogenous IL-4 is required for the induction of CD4+ Th1 protective antifungal responses, possibly through the combined activity on cells of the innate and adaptive immune systems.

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