scholarly journals Effects of CXCL10 on Dendritic Cell and CD4+ T-Cell Functions during Leishmania amazonensis Infection

2007 ◽  
Vol 76 (1) ◽  
pp. 161-169 ◽  
Author(s):  
René E. Vasquez ◽  
Lijun Xin ◽  
Lynn Soong
Keyword(s):  
T Cells ◽  
Progressive Disease ◽  
Inbred Strains ◽  
Leishmania Amazonensis ◽  
Interleukin 12 ◽  
Proinflammatory Response ◽  
Cell Functions ◽  
Inbred Strains Of Mice ◽  
Ifn Γ

ABSTRACT Leishmania amazonensis can cause progressive disease in most inbred strains of mice. We have previously reported that treatment with CXCL10 activates macrophage (MΦ) effector function(s) in parasite killing and significantly delays lesion development in susceptible C57BL/6 mice via enhanced gamma interferon (IFN-γ) and interleukin 12 (IL-12) secretion; however, the mechanism underlying this enhanced immunity against L. amazonensis infection remains largely unresolved. In this study, we utilized stationary promastigotes to infect bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and assessed the activation of DC subsets and the capacity of these DC subsets to prime CD4+ T cells in vitro. We found that CXCL10 induced IL-12 p40 production but reduced IL-10 production in uninfected DCs. Yet L. amazonensis-infected DCs produced elevated levels of IL-10 despite CXCL10 treatment. Elimination of endogenous IL-10 led to increased IL-12 p40 production in DCs as well as increased proliferation and IFN-γ production by in vitro-primed CD4+ T cells. In addition, CXCL10-treated CD4+ T cells became more responsive to IL-12 via increased expression of the IL-12 receptor β2 chain and produced elevated levels of IFN-γ. This report indicates the utility of CXCL10 in generating a Th1-favored, proinflammatory response, which is a prerequisite for controlling Leishmania infection.

scholarly journals CD4+ Th1 Cells Induced by Dendritic Cell-Based Immunotherapy in Mice Chronically Infected with Leishmania amazonensis Do Not Promote Healing

2004 ◽  
Vol 72 (8) ◽  
pp. 4455-4463 ◽  
Author(s):  
Yannick F. Vanloubbeeck ◽  
Amanda E. Ramer ◽  
Fei Jie ◽  
Douglas E. Jones
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Leishmania Amazonensis ◽  
Interleukin 12 ◽  
Mrna Levels ◽  
Antigen Presenting Cell ◽  
Th1 Response ◽  
Ifn Γ ◽  
Antigen Presenting

ABSTRACT The susceptibility of mice to Leishmania amazonensis infection is thought to result from an inability to develop a Th1 response. Our data show that the low levels of gamma interferon (IFN-γ) produced by the draining lymph node (DLN) cells of chronically infected mice could be enhanced in vitro and in vivo with L. amazonensis antigen-pulsed bone marrow-derived dendritic cells (BM-DC) and the Th1-promoting cytokine interleukin-12 (IL-12). Given intralesionally to chronically infected mice, this treatment induced the upregulation of mRNA levels for IFN-γ, the transcription factor T-box expressed in T cells, and IL-12 receptor β2 in CD4+ T cells from the DLN and an increase in parasite-specific immunoglobulin G2a in the serum. However, this Th1 response was not associated with healing, and the antigen-specific enhancement of IFN-γ production remained impaired in the DLN. However, addition of IL-12 to the in vitro recall response was able to recover this defect, suggesting that antigen-presenting cell-derived IL-12 production may be limited in infected mice. This was supported by the fact that L. amazonensis amastigotes limited the production of IL-12p40 from BM-DC in vitro. Altogether, our data indicate that the immune response of mice chronically infected with L. amazonensis can be enhanced towards a Th1 phenotype but that the presence of Th1 CD4+ T cells does not promote healing. This suggests that the phenotype of the CD4+ T cells may not always be indicative of protection to L. amazonensis infection. Furthermore, our data support growing evidence that antigen-presenting cell function, such as IL-12 production, may limit the immune response in L. amazonensis-infected mice.

scholarly journals Interleukin-12 Is the Optimum Cytokine To Expand Human Th17 Cells In Vitro

2009 ◽  
Vol 16 (6) ◽  
pp. 798-805 ◽  
Author(s):  
Soad Nady ◽  
James Ignatz-Hoover ◽  
Mohamed T. Shata
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Interleukin 12 ◽  
Interleukin 17 ◽  
Functional Evaluation ◽  
Optimum Conditions ◽  
T Helper ◽  
Ifn Γ

ABSTRACT Recently, a new lineage of CD4+ T cells in humans and in mice has been reported. This T helper cell secretes interleukin-17 (IL-17) and has been defined as T helper 17 (Th17). Th17 cells express the IL-23 receptor (IL-23R) and play an important pathogenic role in different inflammatory conditions. In this study, our aim was to characterize the optimum conditions for isolation and propagation of human peripheral blood Th17 cells in vitro and the optimum conditions for isolation of Th17 clones. To isolate Th17 cells, two steps were taken. Initially, we negatively isolated CD4+ T cells from peripheral blood mononuclear cells of a normal human blood donor. Then, we isolated the IL-23R+ cells from the CD4+ T cells. Functional studies revealed that CD4+ IL-23R+ cells could be stimulated ex vivo with anti-CD3/CD28 to secrete both IL-17 and gamma interferon (IFN-γ). Furthermore, we expanded the CD4+ IL-23R+ cells for 1 week in the presence of anti-CD3/CD28, irradiated autologous feeder cells, and different cytokines. Our data indicate that cytokine treatment increased the number of propagated cells 14- to 99-fold. Functional evaluation of the expanded number of CD4+ IL-23R+ cells in the presence of different cytokines with anti-CD3/CD28 revealed that all cytokines used (IL-2, IL-7, IL-12, IL-15, and IL-23) increased the amount of IFN-γ secreted by IL-23R+ CD4+ cells at different levels. Our results indicate that IL-7 plus IL-12 was the optimum combination of cytokines for the expansion of IL-23R+ CD4+ cells and the secretion of IFN-γ, while IL-12 preferentially stimulated these cells to secrete predominately IL-17.

scholarly journals In Vivo Clearance of an Intracellular Bacterium, Francisella tularensis LVS, Is Dependent on the p40 Subunit of Interleukin-12 (IL-12) but Not on IL-12 p70

2002 ◽  
Vol 70 (4) ◽  
pp. 1936-1948 ◽  
Author(s):  
Karen L. Elkins ◽  
Allison Cooper ◽  
Susan M. Colombini ◽  
Siobhán C. Cowley ◽  
Tara L. Kieffer
Keyword(s):  
T Cells ◽  
Francisella Tularensis ◽  
Intracellular Bacterium ◽  
Interleukin 12 ◽  
Intracellular Growth ◽  
Lethal Challenge ◽  
Immune Lymphocytes ◽  
Ifn Γ

ABSTRACT To determine the role of interleukin-12 (IL-12) in primary and secondary immunity to a model intracellular bacterium, we have comprehensively evaluated infection with Francisella tularensis LVS in three murine models of IL-12 deficiency. Mice lacking the p40 protein of IL-12 (p40 knockout [KO] mice) and mice treated in vivo with neutralizing anti-IL-12 antibodies survived large doses of primary and secondary LVS infection but never cleared bacteria and exhibited a chronic infection. In dramatic contrast, mice lacking the p35 protein (p35 KO mice) of heterodimeric IL-12 readily survived large doses of primary sublethal LVS infection as well as maximal secondary lethal challenge, with only a slight delay in clearance of bacteria. LVS-immune wild-type (WT) lymphocytes produced large amounts of gamma interferon (IFN-γ), but p35 KO and p40 KO lymphocytes produced much less; nonetheless, similar amounts of NO were found in all cultures containing immune lymphocytes, and all immune lymphocytes were equally capable of controlling intracellular growth of LVS in vitro. Purified CD4+ and CD8+ T cells from both WT and p40 KO mice controlled intracellular growth, even though T cells from WT mice produced much more IFN-γ than those from p40 KO mice, and p40 KO T cells did not adopt a Th2 phenotype. Thus, while IL-12 p70 stimulation of IFN-γ production may be important for bacteriostasis, IL-12 p70 is not necessary for appropriate development of LVS-immune T cells that are capable of controlling intracellular bacterial growth and for clearance of primary or secondary LVS infection. Instead, an additional mechanism dependent on the IL-12 p40 protein, either alone or in another complex such as the newly discovered heterodimer IL-23, appears to be responsible for actual clearance of this intracellular bacterium.

scholarly journals SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

2011 ◽  
Vol 208 (10) ◽  
pp. 2055-2067 ◽  
Author(s):  
Reiko Takahashi ◽  
Shuhei Nishimoto ◽  
Go Muto ◽  
Takashi Sekiya ◽  
Taiga Tamiya ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Responses ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Cell Integrity ◽  
Cell Functions ◽  
Ifn Γ

Regulatory T cells (Treg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of Treg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1−/− Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2−/− mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1−/− Treg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ−/−Socs1−/− Treg cells, the restriction of IFN-γ–STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ−/−Socs1−/− Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ−/−Socs1+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2−/− mice. In vitro experiments suggested that cytokines produced by Socs1−/− Treg cells and Ifnγ−/−Socs1−/− Treg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in Treg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively.

scholarly journals Stimulation of Dendritic Cells via CD40 Enhances Immune Responses to Mycobacterium tuberculosisInfection

2001 ◽  
Vol 69 (4) ◽  
pp. 2456-2461 ◽  
Author(s):  
Caroline Demangel ◽  
Umaimainthan Palendira ◽  
Carl G. Feng ◽  
Andrew W. Heath ◽  
Andrew G. D. Bean ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Protective Efficacy ◽  
Interleukin 12 ◽  
Ifn Γ ◽  
Cellular Immune ◽  
Stimulation Of

ABSTRACT The resolution of pulmonary tuberculosis (TB) critically depends on the development of the Th1 type of immune responses, as exemplified by the exacerbation of TB in IL-12-deficient mice. Therefore, vaccination strategies optimizing IL-12 production by antigen-presenting cells (APC) in response to mycobacteria may have enhanced protective efficacy. Since dendritic cells (DC) are the critical APC for activation of CD4+ and CD8+ T cells, we examined whether stimulation of Mycobacterium bovis bacillus Calmette Guérin (BCG)-infected DC via CD40 increased their ability to generate Th1-oriented cellular immune responses. Incubation of DC with an agonistic anti-CD40 antibody activated CD40 signaling in DC, as shown by increased expression of major histocompatibility complex class II and costimulatory molecules, mRNA production for proinflammatory cytokines and interleukin 12 (IL-12) p40. This activation pattern was maintained when DC were stimulated with anti-CD40 antibody and infected with BCG. Importantly, CD40-stimulated BCG-infected DC displayed increased capacity to release bioactive IL-12 and to activate gamma interferon (IFN-γ) producing T cells in vitro. Moreover, when C57BL/6 mice were immunized with these DC and challenged with aerosol Mycobacterium tuberculosis, increased levels of mRNA for IL-12 p40, IL-18, and IFN-γ were present in the draining mediastinal lymph nodes. However, the mycobacterial burden in the lungs was not reduced compared to that in mice immunized with BCG-infected non-CD40-stimulated DC. Therefore, although the manipulation of DC via CD40 is effective for enhancing immune responses to mycobacteria in vivo, additional strategies are required to increase protection against virulent M. tuberculosis infection.

Vaccines With Interleukin-12–Transduced Acute Myeloid Leukemia Cells Elicit Very Potent Therapeutic and Long-Lasting Protective Immunity

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4263-4273 ◽  
Author(s):  
Kyriaki Dunussi-Joannopoulos ◽  
Kathlene Runyon ◽  
Jamie Erickson ◽  
Robert G. Schaub ◽  
Robert G. Hawley ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 12 ◽  
Ifn Γ ◽  
Acute Myeloid

Abstract Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay between T cells and antigen-presenting cells (APCs). Preclinical studies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor immunity mediated by T cells in several types of tumors. However, the in vivo antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been previously reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is incapable of rescuing mice from lethal leukemia. In contrast, AML cells genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon-γ (IFN-γ), or CD8+ T cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of IFN-γ on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules and induction of the costimulatory molecules B7.1 and B7.2, but no significant direct antiproliferative effect. 51Cr release assays show that rejection of live IL12-AML cells supports the development of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.

scholarly journals Effective Induction of Acquired Resistance to Listeria monocytogenes by Immunizing Mice with In Vivo-Infected Dendritic Cells

2003 ◽  
Vol 71 (1) ◽  
pp. 117-125 ◽  
Author(s):  
Hiroshi Sashinami ◽  
Akio Nakane ◽  
Yoichiro Iwakura ◽  
Mutsuo Sasaki
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Listeria Monocytogenes ◽  
Critical Role ◽  
Acquired Resistance ◽  
Interleukin 12 ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT Splenic dendritic cells (DCs) obtained from mice at 48 h after Listeria monocytogenes infection exhibited up-regulation of CD80 and produced higher titers of gamma interferon (IFN-γ) and interleukin-12 (IL-12) than did DCs obtained from uninfected mice. Mice immunized with DCs obtained from mice that had been infected with L. monocytogenes 48 h before acquired host resistance to lethal infection with L. monocytogenes at 4 and 8 weeks. Immunization with DCs from heat-killed L. monocytogenes failed to induce resistance. Acquired antilisterial resistance is specific, since the immunized mice could not be protected from Salmonella enterica serovar Typhimurium infection. Infected DCs stimulated proliferation of naive CD4+ and CD8+ cells in vitro, suggesting that in vivo-infected DCs activate CD8+ T cells, which are critical in acquired antilisterial resistance, as well as CD4+ T cells. When wild-type mice were immunized with DCs from IFN-γ-deficient mice, they were protected against a lethal L. monocytogenes challenge. In contrast, when mice were immunized with DCs from anti-IL-12 p40 monoclonal antibody-injected mice, they failed to gain acquired antilisterial resistance. These results suggest that DC-derived IL-12, but not IFN-γ, may play a critical role in induction of acquired antilisterial resistance. Our present results suggest that splenic DCs obtained from mice infected with L. monocytogenes in vivo may be an effective immunogen with which to induce antigen-specific immunity.

scholarly journals Antigen-Specific CD8+ T Cells Protect against Lethal Toxoplasmosis in Mice Infected with Neospora caninum

1998 ◽  
Vol 66 (4) ◽  
pp. 1554-1560 ◽  
Author(s):  
Lloyd H. Kasper ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neospora Caninum ◽  
Protozoan Parasite ◽  
Inbred Strains ◽  
Lethal Challenge ◽  
Inbred Strains Of Mice ◽  
High Degree ◽  
Dose Dependent

ABSTRACT Neospora caninum is a coccidial protozoan parasite that appears morphologically indistinguishable from Toxoplasma gondii and that infects a large range of mammals. Both inbred and outbred strains of mice exhibit a high degree of resistance to infection with N. caninum. Three inbred strains of mice (A/J, BALB/c, and C57BL/6) that were infected intraperitoneally withN. caninum were protected against a lethal challenge fromT. gondii. Vaccine-induced protection wasNeospora dose dependent. A rise in the CD8+T-cell population in mice that had been vaccinated with N. caninum and challenged with T. gondii was observed. Adoptive transfer of CD8+ T-cell splenocytes from N. caninum-infected mice was protective against challenge withToxoplasma. The CD8+ T cells fromNeospora-infected mice proliferate to bothNeospora and Toxoplasma antigens in vitro and secrete substantial quantities of gamma interferon when pulsed with the parasite antigen. These observations demonstrate that N. caninum protects against lethal T. gondii infection by the induction of CD8+ T cells that are immunoreactive to both parasites.

Vaccines With Interleukin-12–Transduced Acute Myeloid Leukemia Cells Elicit Very Potent Therapeutic and Long-Lasting Protective Immunity

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4263-4273
Author(s):  
Kyriaki Dunussi-Joannopoulos ◽  
Kathlene Runyon ◽  
Jamie Erickson ◽  
Robert G. Schaub ◽  
Robert G. Hawley ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 12 ◽  
Ifn Γ ◽  
Acute Myeloid

Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay between T cells and antigen-presenting cells (APCs). Preclinical studies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor immunity mediated by T cells in several types of tumors. However, the in vivo antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been previously reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is incapable of rescuing mice from lethal leukemia. In contrast, AML cells genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon-γ (IFN-γ), or CD8+ T cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of IFN-γ on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules and induction of the costimulatory molecules B7.1 and B7.2, but no significant direct antiproliferative effect. 51Cr release assays show that rejection of live IL12-AML cells supports the development of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.

scholarly journals Murine Immune Responses to Liver-Stage Antigen 1 Protein FMP011, a Malaria Vaccine Candidate, Delivered with Adjuvant AS01B or AS02A

2006 ◽  
Vol 75 (2) ◽  
pp. 838-845 ◽  
Author(s):  
Clara Brando ◽  
Lisa A. Ware ◽  
Helen Freyberger ◽  
April Kathcart ◽  
Arnoldo Barbosa ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Cell Types ◽  
Inbred Strains ◽  
Clinical Malaria ◽  
Cell Stage ◽  
Liver Stage ◽  
Inbred Strains Of Mice ◽  
Ifn Γ

ABSTRACT Liver-stage antigen 1 (LSA1) is expressed by Plasmodium falciparum only during the intrahepatic cell stage of the parasite's development. Immunoepidemiological studies in regions where malaria is endemic suggested an association between the level of LSA1-specific humoral and cell-mediated immune responses and susceptibility to clinical malaria. A recombinant LSA1 protein, FMP011, has been manufactured as a preerythrocytic vaccine to induce an immune response that would have the effect of controlling parasitemia and disease in humans. To evaluate the immunogenicity of FMP011, we analyzed the immune response of three inbred strains of mice to antigen immunization using two different adjuvant formulations, AS01B and AS02A. We report here the ability of BALB/c and A/J mice, but not C57BL/6J mice, to mount FMP011-specific humoral (antibody titer) and cellular (gamma interferon [IFN-γ] production) responses following immunization with FMP011 formulated in AS01B or AS02A. Immunization of BALB/c and A/J mice with FMP011/AS01B induced more antigen-specific IFN-γ-producing splenocytes than immunization with FMP011/AS02A. A slightly higher titer of antibody was induced using AS02A than AS01B in both strains. C57BL/6J mice did not respond with any detectable FMP011-specific IFN-γ splenocytes or antibody when immunized with FMP011 in AS01B or AS02A. Intracellular staining of cells isolated from FMP011/AS01B-immunized BALB/c mice indicated that CD4+ cells, but not CD8+ cells, were the main IFN-γ-producing splenocyte. However, inclusion of blocking anti-CD4+ antibody during the in vitro restimulation ELISpot analysis failed to completely abolish IFN-γ production, indicating that while CD4+ T cells were the major source of IFN-γ, other cell types also were involved.

Sign in / Sign up

Export Citation Format

Share Document