IFN-γ–Producing CD4+ T Cells Promote Experimental Cerebral Malaria by Modulating CD8+ T Cell Accumulation within the Brain

AbstractCD8+ T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I)–associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8+ T-cell dysfunction (degranulation and IFN-γ production) and have demonstrated that CD8+ T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-γ in ex vivo unstimulated culture. CD8+ T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer+ cells, but not in CMV pp65 tetramer+ cells. Interestingly, degranulation and IFN-γ production in CD8+ T cells was induced by coculture with autologous CD14+ cells, but not CD4+ T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14+ cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-γ production in infected patients, was enhanced on surface of CD14+ cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8+ T-cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14+ cells in HAM/TSP patients. Despite lower viral expression than in CD4+ T cells, HTLV-I–infected or –activated CD14+ cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients.

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Organ- and Disease-Stage-Specific Regulation of Toxoplasma gondii-Specific CD8-T-Cell Responses by CD4 T Cells

Infection and Immunity ◽

10.1128/iai.00098-06 ◽

2006 ◽

Vol 74 (10) ◽

pp. 5790-5801 ◽

Cited By ~ 26

Author(s):

Sonja Lütjen ◽

Sabine Soltek ◽

Simona Virna ◽

Martina Deckert ◽

Dirk Schlüter

Keyword(s):

T Cells ◽

T Cell ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Functional Activity ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Ifn Γ

ABSTRACT Toxoplasma gondii induces a persistent central nervous system infection, which may be lethally reactivated in AIDS patients with low CD4 T-cell numbers. To analyze the role of CD4 T cells for the regulation of parasite-specific CD8 T cells, mice were infected with transgenic T. gondii expressing the CD8 T-cell antigen β-galactosidase (β-Gal). Depletion of CD4 T cells prior to infection did not affect frequencies of β-Gal876-884-specific (consisting of residues 876 to 884 of β-Gal) CD8 T cells but resulted in a pronounced reduction of intracerebral β-Gal-specific gamma interferon (IFN-γ)-producing and cytolytic CD8 T cells. After cessation of anti-CD4 treatment a normal T. gondii-specific CD4 T-cell response developed, but IFN-γ production of intracerebral β-Gal-specific CD8 T cells remained impaired. The important supportive role of CD4 T cells for the optimal functional activity of intracerebral CD8 T cells was also observed in mice that had been depleted of CD4 T cells during chronic toxoplasmosis. Reinfection of chronically infected mice that had been depleted of CD4 T cells during either the acute or chronic stage of infection resulted in an enhanced proliferation of β-Gal-specific IFN-γ-producing splenic CD8 T cells. However, reinfection of chronically infected mice that had been depleted of CD4 T cells in the acute stage of infection did not reverse the impaired IFN-γ production of intracerebral CD8 T cells. Collectively, these findings illustrate that CD4 T cells are not required for the induction and maintenance of parasite-specific CD8 T cells but, depending on the stage of infection, the infected organ and parasite challenge infection regulate the functional activity of intracerebral CD8 T cells.

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Interplay between IL-10, IFN-γ, IL-17A and PD-1 Expressing EBNA1-Specific CD4+ and CD8+ T Cell Responses in the Etiologic Pathway to Endemic Burkitt Lymphoma

Cancers ◽

10.3390/cancers13215375 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5375

Author(s):

Catherine S. Forconi ◽

David H. Mulama ◽

Priya Saikumar Lakshmi ◽

Joslyn Foley ◽

Juliana A. Otieno ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Burkitt Lymphoma ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

T Cell Response ◽

T Cell Subsets ◽

Effector Memory ◽

Healthy Children ◽

Ifn Γ

Children diagnosed with endemic Burkitt lymphoma (eBL) are deficient in interferon-γ (IFN-γ) responses to Epstein–Barr Nuclear Antigen1 (EBNA1), the viral protein that defines the latency I pattern in this B cell tumor. However, the contributions of immune-regulatory cytokines and phenotypes of the EBNA1-specific T cells have not been characterized for eBL. Using a bespoke flow cytometry assay we measured intracellular IFN-γ, IL-10, IL-17A expression and phenotyped CD4+ and CD8+ T cell effector memory subsets specific to EBNA1 for eBL patients compared to two groups of healthy children with divergent malaria exposures. In response to EBNA1 and a malaria antigen (PfSEA-1A), the three study groups exhibited strikingly different cytokine expression and T cell memory profiles. EBNA1-specific IFN-γ-producing CD4+ T cell response rates were lowest in eBL (40%) compared to children with high malaria (84%) and low malaria (66%) exposures (p < 0.0001 and p = 0.0004, respectively). However, eBL patients did not differ in CD8+ T cell response rates or the magnitude of IFN-γ expression. In contrast, eBL children were more likely to have EBNA1-specific CD4+ T cells expressing IL-10, and less likely to have polyfunctional IFN-γ+IL-10+ CD4+ T cells (p = 0.02). They were also more likely to have IFN-γ+IL-17A+, IFN-γ+ and IL-17A+ CD8+ T cell subsets compared to healthy children. Cytokine-producing T cell subsets were predominantly CD45RA+CCR7+ TNAIVE-LIKE cells, yet PD-1, a marker of persistent activation/exhaustion, was more highly expressed by the central memory (TCM) and effector memory (TEM) T cell subsets. In summary, our study suggests that IL-10 mediated immune regulation and depletion of IFN-γ+ EBNA1-specific CD4+ T cells are complementary mechanisms that contribute to impaired T cell cytotoxicity in eBL pathogenesis.

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γδ-T cells promote IFN-γ–dependent Plasmodium pathogenesis upon liver-stage infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814440116 ◽

2019 ◽

Vol 116 (20) ◽

pp. 9979-9988 ◽

Cited By ~ 10

Author(s):

Julie C. Ribot ◽

Rita Neres ◽

Vanessa Zuzarte-Luís ◽

Anita Q. Gomes ◽

Liliana Mancio-Silva ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cerebral Malaria ◽

Molecular Mechanisms ◽

Critical Role ◽

Γδ T Cells ◽

Experimental Cerebral Malaria ◽

Liver Stage ◽

Ifn Γ ◽

Stage Infection

Cerebral malaria (CM) is a major cause of death due to Plasmodium infection. Both parasite and host factors contribute to the onset of CM, but the precise cellular and molecular mechanisms that contribute to its pathogenesis remain poorly characterized. Unlike conventional αβ-T cells, previous studies on murine γδ-T cells failed to identify a nonredundant role for this T cell subset in experimental cerebral malaria (ECM). Here we show that mice lacking γδ-T cells are resistant to ECM when infected with Plasmodium berghei ANKA sporozoites, the liver-infective form of the parasite and the natural route of infection, in contrast with their susceptible phenotype if challenged with P. berghei ANKA-infected red blood cells that bypass the liver stage of infection. Strikingly, the presence of γδ-T cells enhanced the expression of Plasmodium immunogenic factors and exacerbated subsequent systemic and brain-infiltrating inflammatory αβ-T cell responses. These phenomena were dependent on the proinflammatory cytokine IFN-γ, which was required during liver stage for modulation of the parasite transcriptome, as well as for downstream immune-mediated pathology. Our work reveals an unanticipated critical role of γδ-T cells in the development of ECM upon Plasmodium liver-stage infection.

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Comparison of CD8+ T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria

Frontiers in Immunology ◽

10.3389/fimmu.2019.01747 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 7

Author(s):

Valentina Barrera ◽

Michael J. Haley ◽

Patrick Strangward ◽

Elizabeth Attree ◽

Steve Kamiza ◽

...

Keyword(s):

T Cell ◽

Cerebral Malaria ◽

Cd8 T Cell ◽

Cell Accumulation ◽

The Brain

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Gamma Interferon Responses of CD4 and CD8 T-Cell Subsets Are Quantitatively Different and Independent of Each Other during Pulmonary Mycobacterium bovis BCG Infection

Infection and Immunity ◽

10.1128/iai.00024-07 ◽

2007 ◽

Vol 75 (5) ◽

pp. 2244-2252 ◽

Cited By ~ 26

Author(s):

Patricia Ngai ◽

Sarah McCormick ◽

Cherrie Small ◽

Xizhong Zhang ◽

Anna Zganiacz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cell Activation ◽

Mycobacterial Infection ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) is a key cytokine in host defense against intracellular mycobacterial infection. It has been believed that both CD4 and CD8 T cells are the primary sources of IFN-γ. However, the relative contributions of CD4 and CD8 T-cell subsets to IFN-γ production and the relationship between CD4 and CD8 T-cell activation have not been examined. By using a model of pulmonary mycobacterial infection and various immunodetection assays, we found that CD4 T cells mounted a much stronger IFN-γ response than CD8 T cells at various times after mycobacterial infection, and this pronounced IFN-γ production by CD4 T cells was attributed to both greater numbers of antigen-specific CD4 T cells and a greater IFN-γ secretion capacity of these cells. By using major histocompatibility complex class II-deficient or CD4-deficient mice, we found that the lack of CD4 T cells did not negatively affect primary or secondary CD8 T-cell IFN-γ responses. The CD8 T cells activated in the absence of CD4 T cells were capable of immune protection against secondary mycobacterial challenge. Our results suggest that, whereas both CD4 and CD8 T cells are capable of IFN-γ production, the former represent a much greater cellular source of IFN-γ. Moreover, during mycobacterial infection, CD8 T-cell IFN-γ responses and activation are independent of CD4 T-cell activation.

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IFN-γ from CD4 T Cells Is Essential for Host Survival and Enhances CD8 T Cell Function during Mycobacterium tuberculosis Infection

The Journal of Immunology ◽

10.4049/jimmunol.1200061 ◽

2012 ◽

Vol 190 (1) ◽

pp. 270-277 ◽

Cited By ~ 143

Author(s):

Angela M. Green ◽

Robert DiFazio ◽

JoAnne L. Flynn

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Cd4 T Cells ◽

Cell Function ◽

Cd8 T Cell ◽

Tuberculosis Infection ◽

Mycobacterium Tuberculosis Infection ◽

T Cell Function ◽

Ifn Γ

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Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria

Frontiers in Immunology ◽

10.3389/fimmu.2021.711876 ◽

2021 ◽

Vol 12 ◽

Author(s):

Johanna F. Scheunemann ◽

Julia J. Reichwald ◽

Patricia Jebett Korir ◽

Janina M. Kuehlwein ◽

Lea-Marie Jenster ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cerebral Malaria ◽

Plasmodium Berghei ◽

T Cell Responses ◽

Cytotoxic T Cell ◽

Type I ◽

Experimental Cerebral Malaria ◽

Cell Responses ◽

The Brain

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.

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