Importance of IFN-γ-Mediated Expression of Endothelial VCAM-1 on Recruitment of CD8+T Cells into the Brain During Chronic Infection withToxoplasma gondii

ABSTRACT Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-γ) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-γ-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-γ-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-γ-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-γ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-γ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

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VCAM-1/α4β1 Integrin Interaction Is Crucial for Prompt Recruitment of Immune T Cells into the Brain during the Early Stage of Reactivation of Chronic Infection with Toxoplasma gondii To Prevent Toxoplasmic Encephalitis

Infection and Immunity ◽

10.1128/iai.01494-13 ◽

2014 ◽

Vol 82 (7) ◽

pp. 2826-2839 ◽

Cited By ~ 21

Author(s):

Qila Sa ◽

Eri Ochiai ◽

Tomoko Sengoku ◽

Melinda E. Wilson ◽

Morgan Brogli ◽

...

Keyword(s):

T Cells ◽

Toxoplasma Gondii ◽

Chronic Infection ◽

Early Stage ◽

Toxoplasmic Encephalitis ◽

Mrna Levels ◽

Wild Type ◽

Content Type ◽

Ifn Γ ◽

The Brain

ABSTRACTReactivation of chronic infection withToxoplasma gondiican cause life-threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/α4β1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection. VCAM-1 and ICAM-1 were the endothelial adhesion molecules detected on cerebral vessels of the infected SCID and wild-type animals. Immune T cells from infected wild-type mice were treated with anti-α4 integrin or control antibodies and transferred into infected SCID or nude mice, and the animals received the same antibody every other day. Three days later, sulfadiazine was discontinued to initiate reactivation of infection. Expression of mRNAs for CD3δ, CD4, CD8β, gamma interferon (IFN-γ), and inducible nitric oxide synthase (NOS2) (an effector molecule to inhibitT. gondiigrowth) and the numbers of CD4+and CD8+T cells in the brain were significantly less in mice treated with anti-α4 integrin antibody than in those treated with control antibody at 3 days after sulfadiazine discontinuation. At 6 days after sulfadiazine discontinuation, cerebral tachyzoite-specific SAG1 mRNA levels and numbers of inflammatory foci associated with tachyzoites were markedly greater in anti-α4 integrin antibody-treated than in control antibody-treated animals, even though IFN-γ and NOS2 mRNA levels were higher in the former than in the latter. These results indicate that VCAM-1/α4β1 integrin interaction is crucial for prompt recruitment of immune T cells and induction of IFN-γ-mediated protective immune responses during the early stage of reactivation of chronicT. gondiiinfection to control tachyzoite growth.

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TCR-MHC Interaction Strength Defines Trafficking and Resident Memory Status of CD8 T cells in the Brain

10.1101/263152 ◽

2018 ◽

Author(s):

Anna Sanecka ◽

Nagisa Yoshida ◽

Elizabeth Motunrayo Kolawole ◽

Harshil Patel ◽

Brian D. Evavold ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Chronic Infection ◽

Cd8 T Cell ◽

T Cell Clones ◽

Cell Clones ◽

T Cell Clone ◽

Wide Range ◽

The Brain

AbstractT cell receptor-Major histocompatibility complex (TCR-MHC) affinities span a wide range in a polyclonal T cell response, yet it is undefined how affinity shapes long-term properties of CD8 T cells during chronic infection with persistent antigen. Here, we investigate how the affinity of the TCR-MHC interaction shapes the phenotype of memory CD8 T cells in the chronically Toxoplasma gondii-infected brain. We employed CD8 T cells from three lines of transnuclear (TN) mice that harbour in their endogenous loci different T cell receptors specific for the same Toxoplasma antigenic epitope ROP7. The three TN CD8 T cell clones span a wide range of affinities to MHCI-ROP7. These three CD8 T cell clones have a distinct and fixed hierarchy in terms of effector function in response to the antigen measured as proliferation capacity, trafficking, T cell maintenance and memory formation. In particular, the T cell clone of lowest affinity does not home to the brain. The two higher affinity T cell clones show differences in establishing resident memory populations (CD103+) in the brain with the higher affinity clone persisting longer in the host during chronic infection. Transcriptional profiling of naïve and activated ROP7-specific CD8 T cells revealed that Klf2 encoding a transcription factor that is known to be a negative marker for T cell trafficking is upregulated in the activated lowest affinity ROP7 clone. Our data thus suggest that TCR-MHC affinity dictates memory CD8 T cell fate at the site of infection.

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CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽

10.1182/blood-2002-05-1493 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4253-4259 ◽

Cited By ~ 82

Author(s):

Elodie Belnoue ◽

Michèle Kayibanda ◽

Jean-Christophe Deschemin ◽

Mireille Viguier ◽

Matthias Mack ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Cd8 T Cells ◽

Cytokine Production ◽

Wild Type ◽

Experimental Cerebral Malaria ◽

Pathologic Features ◽

Th1 Cytokine ◽

The Brain ◽

Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

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Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003019 ◽

2021 ◽

Vol 9 (7) ◽

pp. e003019

Author(s):

Robert H Vonderheide ◽

Kimberly A Kraynyak ◽

Anthony F Shields ◽

Autumn J McRee ◽

Jennifer M Johnson ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Cd8 T Cells ◽

Plasmid Dna ◽

Phase 1 ◽

Dna Encoding ◽

Cancer Types ◽

Ifn Γ ◽

Human Telomerase ◽

Disease Free

BackgroundHuman telomerase reverse transcriptase (hTERT) is frequently classified as a ‘universal’ tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types.MethodsA phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type.ResultsOf the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival.ConclusionsPlasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer.

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CD8 T Cells Use IFN-γ To Protect against the Lethal Effects of a Respiratory Poxvirus Infection

The Journal of Immunology ◽

10.4049/jimmunol.1400256 ◽

2014 ◽

Vol 192 (11) ◽

pp. 5415-5425 ◽

Cited By ~ 21

Author(s):

John Goulding ◽

Georges Abboud ◽

Vikas Tahiliani ◽

Pritesh Desai ◽

Tarun E. Hutchinson ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Lethal Effects ◽

Ifn Γ

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Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major

Journal of Experimental Medicine ◽

10.1084/jem.186.7.1137 ◽

1997 ◽

Vol 186 (7) ◽

pp. 1137-1147 ◽

Cited By ~ 255

Author(s):

Sanjay Gurunathan ◽

David L. Sacks ◽

Daniel R. Brown ◽

Steven L. Reiner ◽

Hughes Charest ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Protective Immunity ◽

Leishmania Major ◽

Protective Efficacy ◽

Dna Vaccination ◽

Attractive Alternative ◽

Dna Immunization ◽

Dna Encoding ◽

Ifn Γ

To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-γ (IFN-γ) production. Moreover, both the enhancement of IFN-γ production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8+ T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8+ T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

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NKG2D+ IFN-γ+ CD8+ T Cells Are Responsible for Palladium Allergy

PLoS ONE ◽

10.1371/journal.pone.0086810 ◽

2014 ◽

Vol 9 (2) ◽

pp. e86810 ◽

Cited By ~ 13

Author(s):

Mitsuko Kawano ◽

Masafumi Nakayama ◽

Yusuke Aoshima ◽

Kyohei Nakamura ◽

Mizuho Ono ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Ifn Γ

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Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

Infection and Immunity ◽

10.1128/iai.00943-06 ◽

2006 ◽

Vol 75 (3) ◽

pp. 1154-1166 ◽

Cited By ~ 10

Author(s):

Laura H. Hogan ◽

Dominic O. Co ◽

Jozsef Karman ◽

Erika Heninger ◽

M. Suresh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mycobacterium Bovis ◽

Cd8 T Cells ◽

Bacterial Load ◽

Granulomatous Inflammation ◽

Cd8 T Cell ◽

Activated T Cells ◽

Immunodeficient Mice ◽

Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

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