Gamma Interferon Production by Cytotoxic T Lymphocytes Is Required for Resolution of Chlamydia trachomatis Infection

ABSTRACT In this study, we used mice in which the gene for gamma interferon (IFN-γ) has been disrupted (IFN-γ−/− mice) to study the role of this cytokine in the resolution of Chlamydia trachomatis infection. We show that IFN-γ−/− mice are impaired in the ability to clear infection with C. trachomatis compared to IFN-γ+/+ control mice. Activated CD8+ cytotoxic T lymphocytes (CTL) secrete IFN-γ in response to intracellular infection, and we have shown previously that a Chlamydia-specific CTL line can reduceC. trachomatis infection when adoptively transferred into infected mice. In the present study, we found that when these IFN-γ+/+ CTL lines are transferred intoChlamydia-infected IFN-γ−/− mice, the transferred CTL cannot overcome the immune defect seen in the IFN-γ−/− mice. We also show thatChlamydia-specific CTL can be cultured from IFN-γ-deficient mice infected with C. trachomatis; however, the adoptive transfer of IFN-γ−/− CTL into infected IFN-γ+/+ mice does not reduce the level of infection. These results suggest that IFN-γ production by CTL is not sufficient to overcome the defect that IFN-γ−/− mice have in the resolution of Chlamydia infection, yet IFN-γ production by CTL is required for the protective effect seen upon adoptive transfer of CTL into IFN-γ+/+ mice.

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Gamma Interferon Expression in CD8+ T Cells Is a Marker for Circulating Cytotoxic T Lymphocytes That Recognize an HLA A2-Restricted Epitope of Human Cytomegalovirus Phosphoprotein pp65

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.8.3.628-631.2001 ◽

2001 ◽

Vol 8 (3) ◽

pp. 628-631 ◽

Cited By ~ 38

Author(s):

Smita A. Ghanekar ◽

Laurel E. Nomura ◽

Maria A. Suni ◽

Louis J. Picker ◽

Holden T. Maecker ◽

...

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Human Cytomegalovirus ◽

Surrogate Marker ◽

Gamma Interferon ◽

Strong Positive Correlation ◽

Specific Lysis ◽

Cytokine Flow Cytometry ◽

Ifn Γ

ABSTRACT Antigen-specific CD8+ T cells with cytotoxic activity are often critical in immune responses to infectious pathogens. To determine whether gamma interferon (IFN-γ) expression is a surrogate marker for cytotoxic T lymphocytes (CTL), human cytomegalovirus-specific CTL responses were correlated with CD8+ T-cell IFN-γ expression determined by cytokine flow cytometry. A strong positive correlation was observed between specific lysis of peptide-pulsed targets in a 51Cr release assay and frequencies of peptide-activated CD8+ T cells expressing IFN-γ at 6 h (r 2 = 0.72) or 7 days (r 2 = 0.91). Enumeration of responding cells expressing perforin, another marker associated with CTL, did not improve this correlation. These results demonstrate that IFN-γ expression can be a functional surrogate for identification of CTL precursor cells.

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

Infection and Immunity ◽

10.1128/iai.00847-06 ◽

2006 ◽

Vol 74 (11) ◽

pp. 6252-6263 ◽

Cited By ~ 31

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.

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Identification of Vaccine Candidate Peptides in the NcSRS2 Surface Protein of Neospora caninum by Using CD4+ Cytotoxic T Lymphocytes and Gamma Interferon-Secreting T Lymphocytes of Infected Holstein Cattle

Infection and Immunity ◽

10.1128/iai.73.3.1321-1329.2005 ◽

2005 ◽

Vol 73 (3) ◽

pp. 1321-1329 ◽

Cited By ~ 31

Author(s):

Lauren M. Staska ◽

Christopher J. Davies ◽

Wendy C. Brown ◽

Travis C. McGuire ◽

Carlos E. Suarez ◽

...

Keyword(s):

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

T Lymphocyte ◽

Peripheral Blood ◽

Vaccine Development ◽

Neospora Caninum ◽

Gamma Interferon ◽

Target Cells ◽

Holstein Cattle ◽

Ifn Γ

ABSTRACT Previously, our laboratory showed that Holstein cattle experimentally infected with Neospora caninum develop parasite-specific CD4+ cytotoxic T lymphocytes (CTL) that lyse infected, autologous target cells through a perforin-granzyme pathway. To identify specific parasite antigens inducing bovine CTL and helper T-lymphocyte responses for vaccine development against bovine neosporosis, the tachyzoite major surface proteins NcSAG1 and NcSRS2 were targeted. In whole tachyzoite antigen-expanded bovine T-lymphocyte lines, recombinant NcSRS2 induced potent memory CD4+- and CD8+-T-lymphocyte activation, as indicated by proliferation and gamma interferon (IFN-γ) secretion, while recombinant NcSAG1 induced a minimal memory response. Subsequently, T-lymphocyte epitope-bearing peptides of NcSRS2 were mapped by using overlapping peptides covering the entire NcSRS2 sequence. Four experimentally infected cattle with six different major histocompatibility complex (MHC) class II haplotypes were the source of immune cells used to identify NcSRS2 peptides presented by Holstein MHC haplotypes. NcSRS2 peptides were mapped by using IFN-γ secretion by rNcSRS2-stimulated, short-term T-lymphocyte cell lines, IFN-γ enzyme-linked immunospot (ELISPOT) assay with peripheral blood mononuclear cells, and 51Cr release cytotoxicity assay of rNcSRS2-stimulated effector cells. Four N. caninum-infected Holstein cattle developed NcSRS2 peptide-specific T lymphocytes detected ex vivo in peripheral blood by IFN-γ ELISPOT and in vitro by measuring T-lymphocyte IFN-γ production and cytotoxicity. An immunodominant region of NcSRS2 spanning amino acids 133 to 155 was recognized by CD4+ T lymphocytes from the four cattle. These findings support investigation of subunit N. caninum vaccines incorporating NcSRS2 gene sequences or peptides for induction of NcSRS2 peptide-specific CTL and IFN-γ-secreting T lymphocytes in cattle with varied MHC genotypes.

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Gamma Interferon Dominates the Murine Cytokine Response to the Agent of Human Granulocytic Ehrlichiosis and Helps To Control the Degree of Early Rickettsemia

Infection and Immunity ◽

10.1128/iai.68.4.1827-1833.2000 ◽

2000 ◽

Vol 68 (4) ◽

pp. 1827-1833 ◽

Cited By ~ 66

Author(s):

Mustafa Akkoyunlu ◽

Erol Fikrig

Keyword(s):

Gamma Interferon ◽

Cytokine Response ◽

Interleukin 4 ◽

Infection Model ◽

Granulocytic Ehrlichiosis ◽

Human Granulocytic Ehrlichiosis ◽

Ifn Γ ◽

Immunocompetent Mice ◽

Deficient Mice

ABSTRACT The cytokine response to the agent of human granulocytic ehrlichiosis (HGE) was assessed in a murine infection model and the role of gamma interferon (IFN-γ), a cytokine that is crucial for host defenses against intracellular pathogens, was investigated by using IFN-γ-deficient mice. The agent of HGE (aoHGE) is an obligate intracellular bacterium that survives within neutrophils: morulae (vacuoles containing HGE organisms) are evident in polymorphonuclear leukocytes of experimentally infected immunocompetent mice for 1 to 2 weeks. We now show that IFN-γ levels increase during early infection of C3H/HeN or C57BL/6 mice with HGE bacteria. Moreover, in response to aoHGE extracts or concanavalin A, splenocytes from ehrlichia-infected mice produced more IFN-γ and less interleukin-4 than controls, suggesting that aoHGE partially skewed the immune response towards a Th1 phenotype. Absolute concentration of morulae containing neutrophils in blood was 122 ± 22 cells/μl on day 8. The bacterial DNA burden was also highest on day 8 and then declined after IFN-γ levels peaked. In contrast, IFN-γ-deficient mice had a markedly elevated HGE bacteria burden with morulae concentration of 282 ± 48 cells/μl on day 5 (P = 0.004) and 242 ± 63 cells/μl on day 8 (P = 0.005). Rickettsemia resolved in immunocompetent and IFN-γ deficient mice after 2 weeks, while both the immunocompetent and the IFN-γ-deficient mice had increased serum antibodies against aoHGE antigens at this time point. These data demonstrate that the HGE agent elicits a prominent IFN-γ response in mice and that IFN-γ is important in controlling the degree of rickettsemia during the early phase of infection, while IFN-γ independent mechanisms play a role at later time points.

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Role of Interleukin-4 (IL-4), IL-12, and Gamma Interferon in Primary and Vaccine-Primed Immune Responses to Friend Retrovirus Infection

Journal of Virology ◽

10.1128/jvi.75.2.654-660.2001 ◽

2001 ◽

Vol 75 (2) ◽

pp. 654-660 ◽

Cited By ~ 27

Author(s):

Ulf Dittmer ◽

Karin E. Peterson ◽

Ron Messer ◽

Ingunn M. Stromnes ◽

Brent Race ◽

...

Keyword(s):

Immune Responses ◽

Gamma Interferon ◽

Immunoglobulin M ◽

Friend Virus ◽

T Helper ◽

Friend Retrovirus ◽

Ifn Γ ◽

Deficient Mice ◽

Helper Type

ABSTRACT The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-γ), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4- and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-γ-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-γ-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-γ plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.

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Role of Interleukin-18 in Host Defense against Disseminated Candida albicans Infection

Infection and Immunity ◽

10.1128/iai.70.6.3284-3286.2002 ◽

2002 ◽

Vol 70 (6) ◽

pp. 3284-3286 ◽

Cited By ~ 32

Author(s):

Rogier J. L. Stuyt ◽

Mihai G. Netea ◽

Ineke Verschueren ◽

Giamila Fantuzzi ◽

Charles A. Dinarello ◽

...

Keyword(s):

Candida Albicans ◽

Protective Effect ◽

Host Defense ◽

Gamma Interferon ◽

Interleukin 18 ◽

Ifn Γ ◽

Candida Albicans Infection ◽

Deficient Mice

ABSTRACT In mice injected intravenously with Candida albicans, administration of anti-interleukin-18 (IL-18) antibodies increased the yeast load in the kidneys. There was no effect on the organ load with Candida when gamma interferon (IFN-γ)-deficient mice were treated with anti-IL-18 antibodies, suggesting that the protective effect of IL-18 is mediated through endogenous IFN-γ.

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Increased Host Resistance against Pneumocystis carinii Pneumonia in γδ T-Cell-Deficient Mice: Protective Role of Gamma Interferon and CD8+ T Cells

Infection and Immunity ◽

10.1128/iai.70.9.5208-5215.2002 ◽

2002 ◽

Vol 70 (9) ◽

pp. 5208-5215 ◽

Cited By ~ 47

Author(s):

Chad Steele ◽

Mingquan Zheng ◽

Erana Young ◽

Luis Marrero ◽

Judd E. Shellito ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Pneumocystis Carinii ◽

Lavage Fluid ◽

Gamma Interferon ◽

Host Susceptibility ◽

T Cell Subsets ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT Although a clear relationship between αβ T-cell receptor-positive (αβ-TCR+) CD4+ T cells and susceptibility to Pneumocystis carinii infection exists, the role of other T-cell subsets is less clearly defined. Previous studies have shown that γδ-TCR+ T cells infiltrate into the lung during P. carinii pneumonia. Therefore, the present study examined the role of γδ-TCR+ T cells in host defense against P. carinii pneumonia. C57BL/6 (control) and B6.129P2-Tcrdtm1Mom (γδ-TCR+ T-cell-deficient) mice were inoculated intratracheally with P. carinii. At specific time points, mice were sacrificed and analyzed for P. carinii burden, T-cell subsets, and cytokine levels in lung tissue. Analysis of P. carinii burden showed a more rapid and complete resolution of infection in γδ-TCR+ T-cell-deficient mice than in C57BL/6 controls. This augmented resolution was associated with elevated gamma interferon (IFN-γ) levels in bronchoalveolar lavage fluid predominantly produced by CD8+ T cells, as well as an increased recruitment of CD8+ T cells in general. In separate experiments, neutralization of IFN-γ or depletion of CD8+ T cells early during infection abolished the augmented resolution previously observed in γδ-TCR+ T-cell-deficient mice. These results show that the presence of γδ-TCR+ T cells modulates host susceptibility to P. carinii pneumonia through interactions with pulmonary CD8+ T cells and tissue production of IFN-γ.

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Role of Gamma Interferon in the Pathogenesis of Severe Schistosomiasis in Interleukin-4-Deficient Mice

Infection and Immunity ◽

10.1128/iai.69.12.7445-7452.2001 ◽

2001 ◽

Vol 69 (12) ◽

pp. 7445-7452 ◽

Cited By ~ 16

Author(s):

Anne Camille La Flamme ◽

Elisabeth A. Patton ◽

Edward J. Pearce

Keyword(s):

Severe Disease ◽

Gamma Interferon ◽

Interleukin 4 ◽

No Production ◽

Wild Type ◽

Fatal Disease ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT In the absence of interleukin-4 (IL-4), infection withSchistosoma mansoni leads to a severe fatal disease rather than the chronic survivable condition that occurs in wild-type (WT) mice. Because the sustained production of NO most closely correlates to weight loss and fatality in infected IL-4−/− mice and because gamma interferon (IFN-γ) is an important inducer of inducible NO synthase, infected IL-4−/− mice were treated with anti-IFN-γ antibodies to determine the role of IFN-γ during schistosomiasis in WT and IL-4−/− animals. When IFN-γ was neutralized, Th2 responses were enhanced and NO production was reduced in both WT and IL-4−/− mice. The decreased NO production correlated with a rescue of proliferation in splenocytes from infected IL-4−/− mice. Furthermore, the neutralization of IFN-γ in vivo improved the gross appearance of the liver and led to a reduction in granuloma size in infected IL-4−/− but not WT mice. However, the neutralization of IFN-γ in vivo did not affect the development of severe disease in infected IL-4−/− mice. These results suggest that while the increased production of IFN-γ does lead to some of the pathology observed in infected IL-4−/− mice, it is not ultimately responsible for cachexia and death.

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Role of Gamma Interferon in Controlling Murine Chlamydial Genital Tract Infection

Infection and Immunity ◽

10.1128/iai.67.10.5518-5521.1999 ◽

1999 ◽

Vol 67 (10) ◽

pp. 5518-5521 ◽

Cited By ~ 46

Author(s):

James I. Ito ◽

Joseph M. Lyons

Keyword(s):

Chlamydia Trachomatis ◽

Tract Infection ◽

Genital Tract ◽

Chlamydial Infection ◽

Female Genital Tract ◽

Gamma Interferon ◽

Genital Tract Infection ◽

Ifn Γ ◽

Female Genital

ABSTRACT Earlier investigations have not shown an important role for gamma interferon (IFN-γ) in the early clearance of chlamydial infection from the murine female genital tract. In a model using a human genital isolate of Chlamydia trachomatis in IFN-γ and IFN-γ receptor knockout mice, we were able to demonstrate a major role for IFN-γ in mediating control of infection throughout the course of infection.

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