scholarly journals CD4+ CD25+ Foxp3− T-Regulatory Cells Produce both Gamma Interferon and Interleukin-10 during Acute Severe Murine Spotted Fever Rickettsiosis

2009 ◽  
Vol 77 (9) ◽  
pp. 3838-3849 ◽  
Author(s):  
Rong Fang ◽  
Nahed Ismail ◽  
Thomas Shelite ◽  
David H. Walker
Keyword(s):  
T Cells ◽  
T Regulatory Cells ◽  
Spotted Fever ◽  
Bacterial Load ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Spotted Fever Group ◽  
Regulatory Cells ◽  
Lethal Infection ◽  
Ifn Γ

ABSTRACT Spotted fever group rickettsiae cause life-threatening human infections worldwide. Until now, the immune regulatory mechanisms involved in fatal rickettsial infection have been unknown. C3H/HeN mice infected with 3 × 105 PFU of R ickettsia conorii developed an acute progressive disease, and all mice succumbed to this infection. A sublethal infection induced protective immunity, and mice survived. Compared to splenic T cells from sublethally infected mice, splenic T cells from lethally infected mice produced significantly lower levels of interleukin-2 (IL-2) and gamma interferon (IFN-γ) and a higher level of IL-10, but not of IL-4 or transforming growth factor β, and there was markedly suppressed CD4+ T-cell proliferation in response to antigen-specific stimulation with R. conorii. Furthermore, lethal infection induced significant expansion of CD4+ CD25+ Foxp3− T cells in infected organs compared to the levels in naïve and sublethally infected mice. In a lethal infection, splenic CD4+ CD25+ Foxp3− T cells, which were CTLA-4high T-bet+ and secreted both IFN-γ and IL-10, suppressed the proliferation of and IL-2 production by splenic CD4+ CD25− Foxp3− T cells in vitro. Interestingly, depletion of CD25+ T cells in vivo did not change the disease progression, but it increased the bacterial load in the lung and liver, significantly reduced the number of IFN-γ-producing Th1 cells in the spleen, and increased the serum levels of IFN-γ. These results suggested that CD4+ CD25+ T cells generated in acute murine spotted fever rickettsiosis are Th1-cell-related adaptive T-regulatory cells, which substantially contribute to suppressing the systemic immune response, possibly by a mechanism involving IL-10 and/or cytotoxic T-lymphocyte antigen 4.

scholarly journals Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2–induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 837-845 ◽  
Author(s):  
Guangming Gong ◽  
Lingyun Shao ◽  
Yunqi Wang ◽  
Crystal Y. Chen ◽  
Dan Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treatment Regimen ◽  
T Regulatory Cells ◽  
Mycobacterial Infection ◽  
T Cell Subsets ◽  
Regulatory Cells ◽  
Ifn Γ ◽  
Vγ2vδ2 T Cells

Abstract Although Foxp3+ T regulatory cells (Tregs) are well documented for their ability to suppress various immune cells, T-cell subsets capable of counteracting Tregs have not been demonstrated. Here, we assessed phosphoantigen-activated Vγ2Vδ2 T cells for the ability to interplay with Tregs in the context of mycobacterial infection. A short-term IL-2 treatment regimen induced marked expansion of CD4+CD25+Foxp3+ T cells and subsequent suppression of mycobacterium-driven increases in numbers of Vγ2Vδ2 T cells. Surprisingly, activation of Vγ2Vδ2 T cells by adding phosphoantigen Picostim to the IL-2 treatment regimen down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Consistently, in vitro activation of Vγ2Vδ2 T cells by phosphoantigen plus IL-2 down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Interestingly, anti–IFN-γ–neutralizing antibody, not anti–TGF-β or anti–IL-4, reduced the ability of activated Vγ2Vδ2 T cells to down-regulate Tregs, suggesting that autocrine IFN-γ and its network contributed to Vγ2Vδ2 T cells' antagonizing effects. Furthermore, activation of Vγ2Vδ2 T cells by Picostim plus IL-2 treatment appeared to reverse Treg-driven suppression of immune responses of phosphoantigen-specific IFNγ+ or perforin+ Vγ2Vδ2 T cells and PPD-specific IFNγ+αβ T cells. Thus, phos-phoantigen activation of Vγ2Vδ2 T cells antagonizes IL-2–induced expansion of Tregs and subsequent suppression of Ag-specific antimicrobial T-cell responses in mycobacterial infection.

scholarly journals SA-4-1BBL Costimulation Inhibits Conversion of Conventional CD4+ T Cells into CD4+FoxP3+ T Regulatory Cells by Production of IFN-γ

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e42459 ◽  
Author(s):  
Shravan Madireddi ◽  
Rich-Henry Schabowsky ◽  
Abhishek K. Srivastava ◽  
Rajesh K. Sharma ◽  
Esma S. Yolcu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Regulatory Cells ◽  
Ifn Γ

scholarly journals Aberrant Contraction of Antigen-Specific CD4 T Cells after Infection in the Absence of Gamma Interferon or Its Receptor

2006 ◽  
Vol 74 (11) ◽  
pp. 6252-6263 ◽  
Author(s):  
Jodie S. Haring ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Model Systems ◽  
Important Regulator ◽  
Ifn Γ ◽  
And Function ◽  
Deficient Mice

ABSTRACT Several lines of evidence from different model systems suggest that gamma interferon (IFN-γ) is an important regulator of T-cell contraction after antigen (Ag)-driven expansion. To specifically investigate the role of IFN-γ in regulating the contraction of Ag-specific CD4 T cells, we infected IFN-γ−/− and IFN-γR1−/− mice with attenuated Listeria monocytogenes and monitored the numbers of Ag-specific CD4 T cells during the expansion, contraction, and memory phases of the immune response to infection. In the absence of IFN-γ or the ligand-binding portion of its receptor, Ag-specific CD4 T cells exhibited normal expansion in numbers, but in both strains of deficient mice there was very little decrease in the number of Ag-specific CD4 T cells even at time points later than day 90 after infection. This significant delay in contraction was not due to prolonged infection, since mice treated with antibiotics to conclusively eliminate infection exhibited the same defect in contraction. In addition to altering the number of Ag-specific CD4 T cells, the absence of IFN-γ signaling also changed the phenotype of cells generated after infection. IFN-γR1−/− Ag-specific CD4 T cells reacquired expression of CD127 more quickly than wild-type cells, and more IFN-γR1−/− CD4 T cells were capable of producing both IFN-γ and interleukin 2 following Ag stimulation. From these data we conclude that IFN-γ regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection.

Immune Suppression by Placenta Derived Adherent Cells (PDAC) Correlate with Monocyte Chemoattractant Protein-1 and IL-2 Secretion.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3883-3883
Author(s):  
Casper Paludan ◽  
Ryhor Harbacheuski ◽  
Rose Ann Murray ◽  
Megan Mendillo ◽  
Jorge Soler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Suppression ◽  
T Regulatory Cells ◽  
Interleukin 2 ◽  
Adherent Cells ◽  
Regulatory Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein

Abstract The placenta is a readily available and ethically non-controversial source of large amounts of therapeutic stem cells. Placenta Derived Adherent Cells (PDACs) are isolated from the placenta by one of several methods including physical disruption of tissue from several different anatomical sites within the placenta that include the amniotic membrane, chorion, placental cotyledons, or any combination thereof. Flow cytometry analysis showed that PDACs isolated from certain sites exhibit defined phenotypes, including for example CD200+ CD105+ CD73+ CD34− CD45− at percentages ≥70% and constitutively secrete IL-6, IL-8, and Monocyte Chemoattractant Protein-1 (MCP-1). PDACs demonstrate in vitro pluripotency in the adipogenic, osteogenic, and chondrogenic lineages. Furthermore, PDACs suppress T cell proliferation in certain Mixed Leukocyte Reaction (MLR) and the autologous EBV regression assays. Because secreted factors can powerfully modify immune responses and influence therapeutic use of cells, we report on the cytokine secretion in certain PDAC MLR and regression assays. Cytokines were measured on a Luminex system in supernatants from 6-day PDAC cultures, PDAC MLRs or PDAC regression assays. MLRs include PDACs, Dendritic Cells (DC)s, and T cells at DC/PDAC/T ratios 1/2/10. EBV regression assays included PDACs, EBV antigen-presenting cells (APC), and T cells at APC/PDAC/T ratios 1/2/10. Levels of IL-6 (11 ng/ml) and IL-8 (16 ng/ml) stayed constant in PDAC solo cultures, PDAC MLRs, and PDAC regression assays. MCP-1 concentration was 2 ng/ml in PDAC solo cultures, and non-suppressive control adherent cell MLRs and regression assays, but increased to 10 ng/ml in suppressed PDAC MLRs and PDAC regression assays. These values are consistent with reported MCP-1 serum levels. Interleukin-2 (IL-2) is both a T cell survival factor and an obligate factor for CD4+CD25+ T regulatory cells. T regulatory cells are not required for PDAC T cell suppression, but IL-2 levels consistently increase when MLR suppression by PDACs occurs. The CD4 MLR supernatants contained 65 pg/ml IL-2, and the CD8 MLR contained 35 pg/ml IL-2. In the 85% and 75% suppressed CD4 and CD8 PDAC MLRs, the IL-2 levels rose 5-fold to 331 pg/ml (CD4) and 2-fold to 67 pg/ml(CD8). These results indicate that IL-2 and MCP-1, traditionally known as stimulators of the immune response, may play a role in PDAC immune suppression. PDACs, which cause the secretion, may thus be useful therapeutic tools in the clinic.

scholarly journals Gamma Interferon-Independent Effects of Interleukin-12 on Immunity to Salmonella enterica Serovar Typhimurium

2007 ◽  
Vol 75 (12) ◽  
pp. 5753-5762 ◽  
Author(s):  
Jason D. Price ◽  
Kim R. Simpfendorfer ◽  
Radhakrishnam R. Mantena ◽  
James Holden ◽  
William R. Heath ◽  
...  
Keyword(s):  
T Cells ◽  
Salmonella Enterica ◽  
Bacterial Load ◽  
Bacterial Pathogen ◽  
Cell Receptor ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Mesenteric Lymph Nodes ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACTInterleukin-12 (IL-12) and IL-18 are both central to the induction of gamma interferon (IFN-γ), and various roles for IL-12 and IL-18 in control of intracellular microbial infections have been demonstrated. We used IL-12p40−/−and IL-18−/−mice to further investigate the role of IL-12 and IL-18 in control ofSalmonella entericaserovar Typhimurium. While C57BL/6 and IL-18−/−mice were able to resolve attenuatedS. entericaserovar Typhimurium infections, the IL-12p40−/−mice succumbed to a high bacterial burden after 60 days. Using ovalbumin (OVA)-specific T-cell receptor transgenic T cells (OT-II cells), we demonstrated that following oral infection with recombinantS. entericaserovar Typhimurium expressing OVA, the OT-II cells proliferated in the mesenteric lymph nodes of C57BL/6 and IL-18−/−mice but not in IL-12p40−/−mice. In addition, we demonstrated by flow cytometry that equivalent or increased numbers of T cells produced IFN-γ in IL-12p40−/−mice compared with the numbers of T cells that produced IFN-γ in C57BL/6 and IL-18−/−mice. Finally, we demonstrated that removal of macrophages fromS. entericaserovar Typhimurium-infected C57BL/6 and IL-12p40−/−mice did not affect the bacterial load, suggesting that impaired control ofS. entericaserovar Typhimurium infection in the absence of IL-12p40 is not due to reduced macrophage bactericidal activities, while IL-18−/−mice did rely on the presence of macrophages for control of the infection. Our results suggest that IL-12p40, but not IL-18, is critical to resolution of infections with attenuatedS. entericaserovar Typhimurium and that especially the effects of IL-12p40 on proliferative responses of CD4+T cells, but not the ability of these cells to produce IFN-γ, are important in the resolution of infection by this intracellular bacterial pathogen.

scholarly journals Failure of Gamma Interferon but Not Interleukin-10 Expression in Response to Human Papillomavirus Type 11 E6 Protein in Respiratory Papillomatosis

2004 ◽  
Vol 11 (3) ◽  
pp. 538-547 ◽  
Author(s):  
James A. DeVoti ◽  
Bettie M. Steinberg ◽  
David W. Rosenthal ◽  
Lynda Hatam ◽  
Andrea Vambutas ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Interleukin 2 ◽  
Cytokine Expression ◽  
Gamma Interferon ◽  
Peripheral Blood Mononuclear ◽  
Ifn Γ

ABSTRACT Recurrent respiratory papillomatosis (RRP) is a chronic, debilitating disease of the upper airway caused by human papillomavirus type 6 (HPV-6) or HPV-11. We describe responses of peripheral blood mononuclear cells (PBMC) and T cells from RRP patients and controls to the HPV-11 early proteins E6 and E7. PBMC were exposed in vitro to purified E6 or E7 proteins or transduced with fusion proteins containing the first 11 amino acids of the human immunodeficiency virus type 1 protein tat fused to E6 or E7 (tat-E6/tat-E7). TH1-like (interleukin-2 [IL-2], gamma interferon [IFN-γ], IL-12, and IL-18), and TH2-like (IL-4 and IL-10) cytokine mRNAs were identified by reverse transcription-PCR, and IFN-γ and IL-10 cytokine-producing cells were identified by enzyme-linked immunospot assay. These studies show that HPV-11 E6 skews IL-10-IFN-γ expression by patients with RRP toward greater expression of IL-10 than of IFN-γ. In addition, there is a general cytokine hyporesponsiveness to E6 that is more prominent for TH1-like cytokine expression by patients with severe disease. Patients showed persistent IL-10 cytokine expression by the nonadherent fraction of PBMC when challenged with E6 and tat-E6, and, in contrast to controls, both T cells and non-T cells from patients expressed IL-10. However, E7/tat-E7 cytokine responses in patients with RRP were similar to those of the controls. In contrast, E6 inhibited IL-2 and IL-18 mRNA expression that would further contribute to a cytokine microenvironment unfavorable to HPV-specific, T-cell responses that should control persistent HPV infection. In summary, E6 is the dominant inducer of cytokine expression in RRP, and it induces a skewed expression of IL-10 compared to the expression of IFN-γ.

scholarly journals Gamma Interferon Production by Bovine γδ T Cells following Stimulation with Mycobacterial Mycolylarabinogalactan Peptidoglycan

2004 ◽  
Vol 72 (8) ◽  
pp. 4612-4618 ◽  
Author(s):  
B. Vesosky ◽  
O. C. Turner ◽  
J. Turner ◽  
I. M. Orme
Keyword(s):  
T Cells ◽  
Cell Wall ◽  
Sodium Dodecyl ◽  
Interleukin 2 ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Mycobacterial Cell Wall

ABSTRACT A large percentage of lymphocytes in the blood of cattle express the γδ T-cell receptor, but specific functions for these cells have not yet been clearly defined. There is evidence, however, that human, murine, and bovine γδ T cells have a role in the immune response to mycobacteria. This study investigated the ability of bovine γδ T cells to expand and produce gamma interferon (IFN-γ) in response to stimulation with mycobacterial products. Bovine γδ T cells, isolated from the peripheral blood of healthy cattle, expanded following in vitro stimulation with live mycobacteria, mycobacterial crude cell wall extract, and Mycobacterium bovis culture filtrate proteins. In addition, purified γδ T cells, cocultured with purified monocytes and interleukin-2, consistently produced significant amounts of IFN-γ in response to mycobacterial cell wall. The IFN-γ-inducing component of the cell wall was further identified as a proteolytically resistant, non-sodium dodecyl sulfate-soluble component of the mycolylarabinogalactan peptidoglycan.

scholarly journals Signature for Long-Term Vaccine-Mediated Control of a Simian and Human Immunodeficiency Virus 89.6P Challenge: Stable Low-Breadth and Low-Frequency T-Cell Response Capable of Coproducing Gamma Interferon and Interleukin-2

2005 ◽  
Vol 79 (6) ◽  
pp. 3243-3253 ◽  
Author(s):  
Shanmugalakshmi Sadagopal ◽  
Rama Rao Amara ◽  
David C. Montefiori ◽  
Linda S. Wyatt ◽  
Silvija I. Staprans ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Neutralizing Antibody ◽  
Gamma Interferon ◽  
T Cell Response ◽  
Viral Control ◽  
Immunodeficiency Virus ◽  
Ifn Γ

ABSTRACT In 2001, we reported 20 weeks of control of challenge with the virulent 89.6P chimera of simian and human immunodeficiency viruses (SHIV-89.6P) by a Gag-Pol-Env vaccine consisting of DNA priming and modified vaccinia virus Ankara boosting. Here we report that 22 out of 23 of these animals successfully controlled their viremia until their time of euthanasia at 200 weeks postchallenge. At euthanasia, all animals had low to undetectable viral loads and normal CD4 counts. During the long period of viral control, gamma interferon (IFN-γ)-producing antiviral T cells were present at unexpectedly low breadths and frequencies. Most animals recognized two CD8 and one CD4 epitope and had frequencies of IFN-γ-responding T cells from 0.01 to 0.3% of total CD8 or CD4 T cells. T-cell responses were remarkably stable over time and, unlike responses in most immunodeficiency virus infections, maintained good functional characteristics, as evidenced by coproduction of IFN-γ and interleukin-2. Overall, high titers of binding and neutralizing antibody persisted throughout the postchallenge period. Encouragingly, long-term control was effective in macaques of diverse histocompatibility types.

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