scholarly journals The Absence of Cutaneous Lymph Nodes Results in a Th2 Response and Increased Susceptibility to Leishmania major Infection in Mice

2008 ◽  
Vol 76 (9) ◽  
pp. 4241-4250 ◽  
Author(s):  
Jan M. Ehrchen ◽  
Johannes Roth ◽  
Kirsten Roebrock ◽  
Georg Varga ◽  
Wolfram Domschke ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Leishmania Major ◽  
Systemic Infection ◽  
Th2 Cells ◽  
Th2 Response ◽  
Local Skin ◽  
Critical Requirement ◽  
Β Receptor ◽  
Cellular Immune ◽  
Antigen Presenting

ABSTRACT Lymph nodes (LNs) are important sentinel organs where antigen-presenting cells interact with T cells to induce adaptive immune responses. In cutaneous infection of mice with Leishmania major, resistance depends on the induction of a T-helper-cell-1 (Th1)-mediated cellular immune response in draining, peripheral LNs. We investigated whether draining, peripheral LNs are absolutely required for resistance against L. major infection. We investigated the course of experimental leishmaniasis in wild-type (wt) mice lacking peripheral LNs (pLNs), which we generated by in utero blockade of membrane-bound lymphotoxin, and in mice lacking pLNs or all LNs due to genetic deletion of lymphotoxin ligands or receptors. wt mice of the resistant C57BL/6 strain without local skin-draining LNs were still able to generate specific T-cell responses, but this yielded Th2 cells. This switch to a Th2 response resulted in severe systemic infection. We also confirmed these results with mice lacking pLNs due to genetic depletion of lymphotoxin-β. The complete absence of LNs due to a genetic depletion of the lymphotoxin-β receptor also resulted in a marked deterioration of disease and a Th2 response. Thus, in the absence of pLNs, an L. major-specific Th2 response is induced in the remaining secondary lymphoid organs, such as the spleen and non-skin-draining LNs. This indicates a critical requirement for pLNs to induce protective Th1 immunity and suggests that whether Th1 or Th2 priming to the same antigen occurs depends on the site of the primary antigen recognition.

scholarly journals Immunization with a Toll-Like Receptor 7 and/or 8 Agonist Vaccine Adjuvant Increases Protective Immunity against Leishmania major in BALB/c Mice

2008 ◽  
Vol 76 (8) ◽  
pp. 3777-3783 ◽  
Author(s):  
Wen-Wei Zhang ◽  
Greg Matlashewski
Keyword(s):  
Protective Immunity ◽  
Leishmania Major ◽  
Challenge Infection ◽  
Innate Immune ◽  
Infection Model ◽  
Vaccine Adjuvants ◽  
Th2 Response ◽  
Th1 Response ◽  
Potential Vaccine ◽  
Antigen Presenting

ABSTRACT Activation of Toll-like receptors (TLRs) on antigen-presenting cells of the innate immune system initiates, amplifies, and directs the antigen-specific acquired immune response. Ligands that stimulate TLRs therefore represent potential vaccine adjuvants. In the present study, we determined whether imiquimod and its related compound R848, which are TLR7 and/or TLR8 agonists, represent potential vaccine adjuvants when delivered topically, subcutaneously, or intramuscularly. Using the Leishmania major infection model in BALB/c mice, vaccination with crude Leishmania antigen was not protective against subsequent challenge infection unless it was administered with R848 or a topical application of imiquimod containing cream on the skin. Subcutaneous vaccination with these adjuvants mediated a TH1 response against L. major antigen, which appeared to suppress the TH2 response following a challenge infection. Protective immunity was generated following subcutaneous vaccination but not intramuscular vaccination. These observations suggest that topically administered imiquimod or subcutaneously injected R848 represent potential vaccine adjuvants to enhance the TH1 response, which can be used with existing or new vaccine formulations.

scholarly journals IL-4–producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells

2009 ◽  
Vol 206 (5) ◽  
pp. 1001-1007 ◽  
Author(s):  
Irah L. King ◽  
Markus Mohrs
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Cd4 T Cells ◽  
Helminth Infection ◽  
Th2 Cells ◽  
Mesenteric Lymph Nodes ◽  
Th2 Response ◽  
Tfh Cells ◽  
Follicular Helper

Interleukin (IL)-4 is the quintessential T helper type 2 (Th2) cytokine produced by CD4+ T cells in response to helminth infection. IL-4 not only promotes the differentiation of Th2 cells but is also critical for immunoglobulin (Ig) G1 and IgE isotype-switched antibody responses. Despite the IL-4–mediated link between Th2 cells and B lymphocytes, the location of IL-4–producing T cells in the lymph nodes is currently unclear. Using IL-4 dual reporter mice, we examined the Th2 response and IL-4 production in the draining mesenteric lymph nodes during infection with the enteric nematode Heligmosomoides polygyrus. We show that although IL-4–competent Th2 cells are found throughout the B and T cell areas, IL-4–producing Th2 cells are restricted to the B cell follicles and associate with germinal centers. Consistent with their localization, IL-4 producers express high levels of CXCR5, ICOS, PD-1, IL-21, and BCL-6, a phenotype characteristic of T follicular helper (Tfh) cells. Although IL-4 was dispensable for the generation of Th2 and Tfh cells, its deletion resulted in defective B cell expansion and maturation. Our report reveals the compartmentalization of Th2 priming and IL-4 production in the lymph nodes during infection, and identifies Tfh cells as the dominant source of IL-4 in vivo.

scholarly journals Combined Treatment with Interleukin-12 and Indomethacin Promotes Increased Resistance in BALB/c Mice with Established Leishmania major Infections

2002 ◽  
Vol 70 (10) ◽  
pp. 5715-5720 ◽  
Author(s):  
Jian Li ◽  
Udaikumar M. Padigel ◽  
Phillip Scott ◽  
Jay P. Farrell
Keyword(s):  
Leishmania Major ◽  
Combined Treatment ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
Th2 Response ◽  
Enhanced Production ◽  
Time Of Infection

ABSTRACT Following infection of susceptible BALB/c mice with Leishmania major, early production of interleukin-4 (IL-4) is associated with the development of a nonprotective Th2 response and the development of progressive disease. Treatment of mice with IL-12 at the time of infection can promote the activation of a protective Th1 response; however, IL-12 treatment of mice with established infections has little effect on the progress of lesion development. This may be due to a down-regulation of the IL-12 receptor β2 chain (IL-12Rβ2) that accompanies the expansion of IL-4-producing Th2 cells. We have examined whether prostaglandins function to regulate in vivo responsiveness to IL-12. Mice treated with indomethacin are responsive to treatment with exogenous IL-12 through at least the first 2 weeks of infection and, unlike control mice treated with IL-12, develop an enhanced Th1-type response associated with increased enhanced resistance to infection. Cells from indomethacin-treated mice also exhibit enhanced production of gamma interferon (IFN-γ) following in vitro stimulation with IL-12. Although in vivo indomethacin treatment did not appear to influence IL-12 production in infected mice, cells from indomethacin-treated mice did express higher levels of IL-12Rβ2, suggesting that prostaglandins may play a role in the loss of IL-12 responsiveness observed during nonhealing L. major infections.

scholarly journals In the Absence of CD154, Administration of Interleukin-12 Restores Th1 Responses but Not Protective Immunity to Schistosoma mansoni

2007 ◽  
Vol 75 (7) ◽  
pp. 3539-3547 ◽  
Author(s):  
James P. Hewitson ◽  
Paul A. Hamblin ◽  
Adrian P. Mountford
Keyword(s):  
Lymph Nodes ◽  
Protective Immunity ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Cellular Immune ◽  
Antigen Presenting ◽  
Induced Immunity

ABSTRACT The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154−/− mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154−/− mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154−/− mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154−/− mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154−/− mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c+ cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154−/− mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.

scholarly journals Identification of Two Distinct Subpopulations of Leishmania major-Specific T Helper 2 Cells

2002 ◽  
Vol 70 (10) ◽  
pp. 5512-5520 ◽  
Author(s):  
Pascale Kropf ◽  
Shanti Herath ◽  
Rita Tewari ◽  
Nelofer Syed ◽  
Roman Klemenz ◽  
...  
Keyword(s):  
T Cells ◽  
Leishmania Major ◽  
Lymphoid Organs ◽  
Cytokine Profile ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th2 Response ◽  
T Helper 2

ABSTRACT It is widely accepted that a strong Th2 response is responsible for nonhealing Leishmania major infections in BALB/c mice. This Th2 response has been thoroughly documented by measuring the levels of Th2 cytokines produced by CD4+ T cells present in the lymphoid organs by enzyme-linked immunosorbent assay and PCR. However, the cytokine profile of L. major-specific Th2 cells has never been determined. In this study, we used the recently described Th2 marker T1/ST2 to characterize Th2 cells during the course of nonhealing L. major infection. We analyzed the intracellular cytokine profile of CD4+ T1/ST2+ T cells and showed that they clearly displayed a Th2 phenotype, as they expressed interleukin 4 (IL-4), IL-10, and IL-5. In addition, we detected another population of Th2 cells among the CD4+ T1/ST2− T cells that expressed IL-4 and IL-10 but excluded IL-5. In summary, we show here that two type 2 subpopulations are present in the lymphoid organs of L. major-infected BALB/c mice; Th2 cells from both subsets expressed IL-4 and IL-10, but they could be distinguished by their expression of IL-5 and T1/ST2.

scholarly journals SERPINB10 contributes to asthma by inhibiting the apoptosis of allergenic Th2 cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuqing Mo ◽  
Ling Ye ◽  
Hui Cai ◽  
Guiping Zhu ◽  
Jian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Allergic Asthma ◽  
Cd4 T Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Allergic Inflammation ◽  
Specific Ige ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th2 Response ◽  
Th1 And Th2

Abstract Background Serine peptidase inhibitor, clade B, member 10 (SERPINB10) contributes to allergic inflammation in asthma. However, its role in the T-helper type 2 (Th2) response of allergic asthma is not known. The goal of this study was to unveil the function of SERPINB10 in the Th2 response of allergic asthma and the mechanism by which SERPINB10 affects the viability of Th2 cells. Methods Th2 cytokines and serum levels of house dust mite (HDM)-specific IgE in bronchoalveolar lavage fluid were examined by ELISA in an HDM-induced asthma model. The number and apoptosis of Th1 and Th2 cells in mouse lungs were measured by flow cytometry. Naïve CD4 T cells from patients with asthma were cultured under appropriate polarizing conditions to generate Th1 and Th2 cells. SERPINB10 expression in polarized Th1 and Th2 cells was quantified by real-time reverse transcription-quantitative polymerase chain reaction. SERPINB10 expression was knocked down in human CD4 T cells with lentivirus. Results Knockdown of SERPINB10 expression significantly diminished HDM-induced Th2 cytokine secretion and level of HDM-specific IgE. After HDM exposure, SERPINB10-knockdown mice had diminished numbers of Th2 cells, but similar numbers of Th1 cells, compared with those in negative-control mice. Th2 cells of SERPINB10-knockdown mice were more susceptible to apoptosis than that of control mice. Stimulating T-cell receptors (TCRs) with anti-CD3 antibody caused upregulation of SERPINB10 expression in polarized Th2 cells, but not polarized Th1 cells. Knockdown of SERPINB10 expression resulted in fewer numbers and greater apoptosis of polarized Th2 cells. Conclusion Our results suggest that SERPINB10 may contribute to allergic inflammation and the Th2 response of asthma by inhibiting the apoptosis of Th2 cells.

scholarly journals Hierarchy of Susceptibility of Dendritic Cell Subsets to Infection by Leishmania major: Inverse Relationship to Interleukin-12 Production

2002 ◽  
Vol 70 (7) ◽  
pp. 3874-3880 ◽  
Author(s):  
Sandrine Henri ◽  
Joan Curtis ◽  
Hubertus Hochrein ◽  
David Vremec ◽  
Ken Shortman ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mhc Class Ii ◽  
Leishmania Major ◽  
Parasitophorous Vacuole ◽  
Class Ii ◽  
Host Cells ◽  
Interleukin 12 ◽  
Histocompatibility Complex ◽  
T Cell Immune Responses ◽  
Antigen Presenting

ABSTRACT Dendritic cells (DCs) are professional antigen-presenting cells which initiate and regulate T-cell immune responses. Here we show that murine splenic DCs can be ranked on the basis of their ability to phagocytose and harbor the obligately intracellular parasite Leishmania major. CD4+ CD8− DCs are the most permissive host cells for L. major amastigotes, followed by CD4− CD8− DCs; CD4− CD8+ cells are the least permissive. However, the least susceptible CD4− CD8+ DC subset was the best interleukin-12 producer in response to infection. Infection did not induce in any DC subset production of the proinflammatory cytokine gamma interferon and nitric oxide associated with the induction of Th1 responses. The number of parasites phagocytosed by DCs was low, no more than 3 organisms per cell, compared to more than 10 organisms per macrophage. In infected DCs, the parasites are located in a parasitophorous vacuole containing both major histocompatibility complex (MHC) class II and lysosome-associated membrane protein 1 molecules, similar to their location in the infected macrophage. The parasite-driven redistribution of MHC class II to this compartment indicates that infected DCs should be able to present parasite antigen.

Sign in / Sign up

Export Citation Format

Share Document