scholarly journals Langerhans cells are negative regulators of the anti-Leishmania response

2011 ◽  
Vol 208 (5) ◽  
pp. 885-891 ◽  
Author(s):  
Kordula Kautz-Neu ◽  
Madelon Noordegraaf ◽  
Stephanie Dinges ◽  
Clare L. Bennett ◽  
Dominik John ◽  
...  
Keyword(s):  
Langerhans Cells ◽  
Protective Immunity ◽  
Low Dose ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Cell Ablation ◽  
Selective Depletion ◽  
T Cell Immune Responses

Migratory skin dendritic cells (DCs) are thought to play an important role in priming T cell immune responses against Leishmania major, but DC subtypes responsible for the induction of protective immunity against this pathogen are still controversial. In this study, we analyzed the role of Langerin+ skin-derived DCs in the Leishmania model using inducible in vivo cell ablation. After physiologically relevant low-dose infection with L. major (1,000 parasites), mice depleted of all Langerin+ DCs developed significantly smaller ear lesions with decreased parasite loads and a reduced number of CD4+ Foxp3+ regulatory T cells (T reg cells) as compared with controls. This was accompanied by increased interferon γ production in lymph nodes in the absence of Langerin+ DCs. Moreover, selective depletion of Langerhans cells (LCs) demonstrated that the absence of LCs, and not Langerin+ dermal DC, was responsible for the reduced T reg cell immigration and the enhanced Th1 response, resulting in attenuated disease. Our data reveal a unique and novel suppressive role for epidermal LCs in L. major infection by driving the expansion of T reg cells. A better understanding of the various roles of different DC subsets in cutaneous leishmaniasis will improve the development of a potent therapeutic/prophylactic vaccine.

scholarly journals Low Dose Leishmania major Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon γ–producing CD8+ T Cells

2004 ◽  
Vol 199 (11) ◽  
pp. 1559-1566 ◽  
Author(s):  
Jude E. Uzonna ◽  
Karen L. Joyce ◽  
Phillip Scott
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Low Dose ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Th2 Response ◽  
Th1 Response ◽  
Th Cell

An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite. Here we resolve this paradox by studying the early immune response in mice after infection with different doses of Leishmania major. We found that low parasite doses induced a Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response. However, the Th2 response in low dose–infected mice was transient and the animals healed. The appearance of a Th1 response after low dose infection was dependent upon the concomitant activation of interferon γ–producing CD8+ T cells. In the absence of CD8+ T cells, the Th2 response was maintained. However, either neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1 response after low dose infection of CD8-deficient mice, indicating that the required role for CD8+ T cells was limited to modulation of CD4+ T cell responses. Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response.

scholarly journals Comparisons of Mutants Lacking the Golgi UDP-Galactose or GDP-Mannose Transporters Establish that Phosphoglycans Are Important for Promastigote but Not Amastigote Virulence in Leishmania major

2007 ◽  
Vol 75 (9) ◽  
pp. 4629-4637 ◽  
Author(s):  
Althea A. Capul ◽  
Suzanne Hickerson ◽  
Tamara Barron ◽  
Salvatore J. Turco ◽  
Stephen M. Beverley
Keyword(s):  
Golgi Apparatus ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Protozoan Parasite ◽  
Macrophage Infection ◽  
Nucleotide Sugar ◽  
Infectious Cycle ◽  
Null Mutants

ABSTRACT Abundant surface Leishmania phosphoglycans (PGs) containing [Gal(β1,4)Man(α1-PO4)]-derived repeating units are important at several points in the infectious cycle of this protozoan parasite. PG synthesis requires transport of activated nucleotide-sugar precursors from the cytoplasm to the Golgi apparatus. Correspondingly, null mutants of the L. major GDP-mannose transporter LPG2 lack PGs and are severely compromised in macrophage survival and induction of acute pathology in susceptible mice, yet they are able to persist indefinitely and induce protective immunity. However, lpg2 − L. mexicana amastigotes similarly lacking PGs but otherwise normal in known glycoconjugates remain able to induce acute pathology. To explore this further, we tested the infectivity of a new PG-null L. major mutant, which is inactivated in the two UDP-galactose transporter genes LPG5A and LPG5B. Surprisingly this mutant did not recapitulate the phenotype of L. major lpg2 −, instead resembling the L. major lipophosphoglycan-deficient lpg1 − mutant. Metacyclic lpg5A −/lpg5B − promastigotes showed strong defects in the initial steps of macrophage infection and survival. However, after a modest delay, the lpg5A − /lpg5B − mutant induced lesion pathology in infected mice, which thereafter progressed normally. Amastigotes recovered from these lesions were fully infective in mice and in macrophages despite the continued absence of PGs. This suggests that another LPG2-dependent metabolite is responsible for the L. major amastigote virulence defect, although further studies ruled out cytoplasmic mannans. These data thus resolve the distinct phenotypes seen among lpg2 − Leishmania species by emphasizing the role of glycoconjugates other than PGs in amastigote virulence, while providing further support for the role of PGs in metacyclic promastigote virulence.

scholarly journals Cross-reactive, natural IgG recognizing L. major promote parasite internalization by dendritic cells and promote protective immunity

2021 ◽  
Author(s):  
Filiz Dermicik ◽  
Susanna Lopez Kostka ◽  
Stefan Tenzer ◽  
Ari Waisman ◽  
Esther Von Stebut
Keyword(s):  
Dendritic Cells ◽  
B Cell ◽  
Protective Immunity ◽  
Normal Mouse ◽  
Leishmania Major ◽  
Mouse Serum ◽  
List Type ◽  
Susceptibility To Infection ◽  
Large Numbers

Abstract In cutaneous leishmaniasis, infection of dendritic cells (DC) is essential for generation of T cell-dependent protective immunity. DC acquires Leishmania major through Fc receptor (FcR)-mediated uptake of complexes comprising antibodies bound to parasites. We now assessed the development of the initial B cell and DC response to the parasite itself and if natural IgG play a role. L. major parasites display large numbers of phospholipids on their surface. Parasites were opsonized with normal mouse serum (NMS), or serum containing anti-phospholipid IgG (PL). We found that L. major bound to PL which significantly enhanced parasite phagocytosis by DC as compared to NMS. Similar results were obtained with cross-reactive human PL antibodies using myeloid primary human DC. In addition, mice infected with PL-opsonized parasites showed significantly improved disease outcome compared to mice infected with NMS-opsonized parasites. Finally, IgMi mice, which produce membrane-bound IgM only and no secreted antibodies, displayed increased susceptibility to infection as compared to wild types. Interestingly, once NMS was administered to IgMi mice, their phenotype was normalized to that of wild types. Upon incubation with IgG-opsonized parasite (IgG derived from infected mice or using PL antibodies), also the IgMi mice were able to show superior immunity. Our findings suggest that “natural” cross-reactive antibodies (e.g., anti-PL Ab) in NMS bind to pathogens to facilitate phagocytosis, which leads to induction of protective immunity via preferential DC infection. Prior L. major-specific B cell-priming does not seem to be absolutely required to facilitate clearance of this important human pathogen in vivo. Key messages We found that anti-phospholipid (anti-PL) antibodies enhance phagocytosis of L. major by DCs. We also found that normal mouse sera have natural antibodies that can imitate PL specific antibodies. Using different genetically modified mice, we found that these antibodies can be IgG, not only IgM.

scholarly journals Chronic Microcystin-LR Exposure Induces Hepatocarcinogenesis via Increased Gankyrin in Vitro and in Vivo

2018 ◽  
Vol 49 (4) ◽  
pp. 1420-1430 ◽  
Author(s):  
Lixiong He ◽  
Yujing Huang ◽  
Qiaonan Guo ◽  
Hui Zeng ◽  
Chuanfen Zheng ◽  
...  
Keyword(s):  
Low Dose ◽  
Soft Agar ◽  
Tumor Formation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
L02 Cells ◽  
Insight Into

Background/Aims: Our recent study indicated that the serum microcystin-LR (MC-LR) level is positively linked to the risk of human hepatocellular carcinoma (HCC). Gankyrin is over-expressed in cancers and mediates oncogenesis; however, whether MC-LR induces tumor formation and the role of gankyrin in this process is unclear. Methods: We induced malignant transformation of L02 liver cells via 35 passages with exposure to 1, 10, or 100 nM MC-LR. Wound healing, plate and soft agar colony counts, and nude mice tumor formation were used to evaluate the tumorigenic phenotype of MC-LR-treated cells. Silencing gankyrin was used to confirm its function. We established a 35-week MC-LR exposure rat model by twice weekly intraperitoneal injection with 10 μg/kg body weight. In addition, 96 HCC patients were tested for tumor tissue gankyrin expression and serum MC-LR levels. Results: Chronic low-dose MC-LR exposure increased proliferation, mobility, clone and tumor formation abilities of L02 cells as a result of gankyrin activation, while silencing gankyrin inhibited the carcinogenic phenotype of MC-LR-treated cells. MC-LR also induced neoplastic liver lesions in Sprague-Dawley rats due to up-regulated gankyrin. Furthermore, a trend of increased gankyrin was observed in humans exposed to MC-LR. Conclusion: These results suggest that MC-LR induces hepatocarcinogenesis in vitro and in vivo by increasing gankyrin levels, providing new insight into MC-LR carcinogenicity studies.

scholarly journals Interleukin 1α Promotes Th1 Differentiation and Inhibits Disease Progression in Leishmania major–susceptible BALB/c Mice

2003 ◽  
Vol 198 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Esther von Stebut ◽  
Jan M. Ehrchen ◽  
Yasmine Belkaid ◽  
Susanna Lopez Kostka ◽  
Katharina Mölle ◽  
...  
Keyword(s):  
Disease Progression ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Mouse Strains ◽  
Mrna Accumulation ◽  
Partial Explanation ◽  
Th2 Cytokine ◽  
Local Injections ◽  
Interleukin 1Α

Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12–dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1α in response to lipopolysaccharide/interferon γ or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1α mRNA accumulation in lymph nodes of L. major–infected BALB/c mice was ∼3-fold lower than that in C57BL/6 mice. Local injections of IL-1α during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major–infected BALB/c mice, IL-1α administration resulted in increased Th1- and strikingly decreased Th2-cytokine production. IL-1α and IL-12 treatments were similarly effective, and IL-1α efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1α acts in conjunction with IL-12 to influence Th-development in cutaneous leishmaniasis and prevents disease progression in susceptible BALB/c mice, perhaps by enhancing DC-induced Th1-education. Differential production of IL-1 by C57BL/6 and BALB/c mice may provide a partial explanation for the disparate outcomes of infection in these mouse strains.

scholarly journals IL-27 promotes T cell–dependent colitis through multiple mechanisms

2010 ◽  
Vol 208 (1) ◽  
pp. 115-123 ◽  
Author(s):  
Jennifer H. Cox ◽  
Noelyn M. Kljavin ◽  
Nandhini Ramamoorthi ◽  
Lauri Diehl ◽  
Marcel Batten ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Interferon Γ ◽  
Transfer Model ◽  
Proinflammatory Role ◽  
Immune Pathology

Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor α (Il27ra)–deficient mice suffer from exacerbated immune pathology when infected with various parasites or challenged with autoantigens. Because the role of IL-27 in human and experimental mouse colitis is controversial, we studied the consequences of Il27ra deletion in the mouse T cell transfer model of colitis and unexpectedly discovered a proinflammatory role of IL-27. Absence of Il27ra on transferred T cells resulted in diminished weight loss and reduced colonic inflammation. A greater fraction of transferred T cells assumed a Foxp3+ phenotype in the absence of Il27ra, suggesting that IL-27 functions to restrain regulatory T cell (Treg) development. Indeed, IL-27 suppressed Foxp3 induction in vitro and in an ovalbumin-dependent tolerization model in vivo. Furthermore, effector cell proliferation and IFN-γ production were reduced in the absence of Il27ra. Collectively, we describe a proinflammatory role of IL-27 in T cell–dependent intestinal inflammation and provide a rationale for targeting this cytokine in pathological situations that result from a breakdown in peripheral immune tolerance.

scholarly journals Depletion of CD8+ T Cells In Vivo Impairs Host Defense of Mice Resistant and Susceptible to Pulmonary Paracoccidioidomycosis

2000 ◽  
Vol 68 (1) ◽  
pp. 352-359 ◽  
Author(s):  
Luz E. Cano ◽  
Lúcia M. Singer-Vermes ◽  
Tania A. Costa ◽  
José O. Mengel ◽  
Cynthia F. Xidieh ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
Paracoccidioides Brasiliensis ◽  
Delayed Type Hypersensitivity ◽  
Mouse Strains ◽  
Fungal Load ◽  
Granulomatous Lesions ◽  
Selective Depletion

ABSTRACT Using a pulmonary model of infection, we demonstrated previously that A/Sn and B10.A mice are, respectively, resistant and susceptible to Paracoccidioides brasiliensis infection. Employing the same experimental model, we examined herein the role of CD8+ T cells in the course of paracoccidioidomycosis. Treatment with anti-CD8 monoclonal antibodies caused a selective depletion of pulmonary and splenic CD8+ T cells in both mouse strains. The number of pulmonary CD4+ T cells and immunoglobulin-positive cells was independent of the number of CD8+ T cells. In susceptible mice, the loss of CD8+ T cells by in vivo treatment with anti-CD8 monoclonal antibodies impaired the clearance of yeasts from the lungs and increased the fungal dissemination to the liver and spleen. The same treatment in resistant mice increased fungal dissemination to extrapulmonary tissues but did not alter the pulmonary fungal load. Furthermore, CD8+ T-cell depletion did not modify delayed-type hypersensitivity reactions of A/Sn mice but increased these reactions in B10.A mice. The production of P. brasiliensis-specific antibodies by resistant and susceptible mice depleted of CD8+ T cells was similar to that of mice given control antibody. Histopathologically, depletion of CD8+ T cells did not disorganize the focal granulomatous lesions developed by both mouse strains. These results indicate that CD8+ T cells are necessary for optimal clearance of the fungus from tissues of mice infected with P. brasiliensisand demonstrate more prominent protective activity by those cells in the immune responses mounted by susceptible animals.

scholarly journals IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 2023-2031 ◽  
Author(s):  
Anja Fröhlich ◽  
Benjamin J. Marsland ◽  
Ivo Sonderegger ◽  
Michael Kurrer ◽  
Martin R. Hodge ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Allergic Airway Inflammation ◽  
Nippostrongylus Brasiliensis ◽  
Autoimmune Myocarditis ◽  
Heligmosomoides Polygyrus ◽  
Peripheral Tissues ◽  
Th2 Cell ◽  
Th2 Responses

Abstract Interleukin 21 (IL-21) is a member of the common γ-chain family of cytokines, which influence a broad spectrum of immunologic responses. A number of studies have examined the function of IL-21, but its specific role in Th1/Th2-cell differentiation and related effector responses remains to be clarified. Thus, we generated IL-21R–deficient mice and have investigated the role of IL-21R signaling using a series of in vivo experimentally induced disease models. We first addressed the role of IL-21R signaling in Th2 immune responses by examining allergic airway inflammation, and Nippostrongylus brasiliensis and Heligmosomoides polygyrus antihelminth responses. In each of these systems, IL-21R signaling played a clear role in the development of Th2 responses. Comparatively, IL-21R signaling was not required for the containment of Leishmania major infection or the development of experimental autoimmune myocarditis, indicative of competent Th1 and Th17 responses, respectively. Adoptive transfer of T cells and analysis of IL-21R+/+/IL-21R−/− chimera mice revealed that IL-21R–signaling was central to Th2-cell survival or migration to peripheral tissues. Overall, our data show IL-21 plays a crucial role in supporting polarized Th2 responses in vivo, while appearing superfluous for Th1 and Th17 responses.

scholarly journals Induction of Protective Immunity to Listeria monocytogenes by Immunization with Plasmid DNA Expressing a Helper T-Cell Epitope That Replaces the Class II-Associated Invariant Chain Peptide of the Invariant Chain

2002 ◽  
Vol 70 (5) ◽  
pp. 2676-2680 ◽  
Author(s):  
Toshi Nagata ◽  
Taiki Aoshi ◽  
Mina Suzuki ◽  
Masato Uchijima ◽  
Yeung-Hyen Kim ◽  
...  
Keyword(s):  
Plasmid Dna ◽  
Protective Immunity ◽  
Interleukin 2 ◽  
Cell Epitope ◽  
Class Ii ◽  
Interferon Γ ◽  
Invariant Chain ◽  
T Cell Epitope ◽  
Th Cells

ABSTRACT Listeria epitope-specific helper T (Th) cells were able to be primed and induced in vivo by immunization with a plasmid carrying an invariant chain (Ii) gene whose class II-associated invariant chain peptide (CLIP) region was replaced by a Listeria Th epitope. Immunization of C3H/He mice with an Ii-LLO 215-226 plasmid induced specific interferon-γ- and interleukin 2-producing Th cells and conferred significant protective immunity against listerial infection.

Sign in / Sign up

Export Citation Format

Share Document