TLR11-independent inflammasome activation is critical for CD4+ T cell-derived IFN-γ production and host resistance to Toxoplasma gondii

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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TAP-1 indirectly regulates CD4+ T cell priming in Toxoplasma gondii infection by controlling NK cell IFN-γ production

Journal of Experimental Medicine ◽

10.1084/jem.20070634 ◽

2007 ◽

Vol 204 (11) ◽

pp. 2591-2602 ◽

Cited By ~ 55

Author(s):

Romina S. Goldszmid ◽

Andre Bafica ◽

Dragana Jankovic ◽

Carl G. Feng ◽

Pat Caspar ◽

...

Keyword(s):

T Cell ◽

Toxoplasma Gondii ◽

Nk Cells ◽

Antigen Processing ◽

Nk Cell ◽

T Cell Response ◽

Cd4 T Cell ◽

Ifn Γ ◽

Toxoplasma Gondii Infection

To investigate if transporter associated with antigen processing (TAP)–1 is required for CD8+ T cell–mediated control of Toxoplasma gondii in vivo, we compared the resistance of TAP-1−/−, CD8−/−, and wild-type (WT) mice to infection with the parasite. Unexpectedly, TAP-1−/− mice displayed greater susceptibility than CD8−/−, β2-microglobulin−/− (β2m−/−), or WT mice to infection with an avirulent parasite strain. The decreased resistance of the TAP-1−/− mice correlated with a reduction in the frequency of activated (CD62Llow CD44hi) and interferon (IFN)-γ–producing CD4+ T cells. Interestingly, infected TAP-1−/− mice also showed reduced numbers of IFN-γ–producing natural killer (NK) cells relative to WT, CD8−/−, or β2m−/− mice, and after NK cell depletion both CD8−/− and WT mice succumbed to infection with the same kinetics as TAP-1−/− animals and displayed impaired CD4+ T cell IFN-γ responses. Moreover, adoptive transfer of NK cells obtained from IFN-γ+/+, but not IFN-γ−/−, animals restored the CD4+ T cell response of infected TAP-1−/− mice to normal levels. These results reveal a role for TAP-1 in the induction of IFN-γ–producing NK cells and demonstrate that NK cell licensing can influence host resistance to infection through its effect on cytokine production in addition to its role in cytotoxicity.

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The Effect of Antiretroviral Therapy on IL-6, IL-1β, TNF-α, IFN-γ Levels and their Relationship with HIV-RNA and CD4+ T Cells in HIV Patients

Current HIV Research ◽

10.2174/1570162x18666200712174642 ◽

2020 ◽

Vol 18 (5) ◽

pp. 354-361

Author(s):

Gülay Okay ◽

Meliha Meric Koc ◽

Eray Metin Guler ◽

Ayşegül Yabaci ◽

Abdürrahim Kocyigit ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

Cell Count ◽

Cd4 T Cell ◽

Positive Correlation ◽

Hiv Rna ◽

Tnf Α ◽

Cytokine Levels ◽

Ifn Γ ◽

Cd4 T Cell Count

Background: Serum cytokine levels over the course of HIV infection usually increase with immunosuppression and decrease after antiretroviral treatment (ART). Objectives: The aim of the study is to compare cytokine levels between HIV-infected patients (HIP) and controls and investigate the relationship between CD4+T cell count, HIV-RNA levels, and cytokine levels. Methods: The study subjects comprised ART-naive HIP (n=30) with no comorbidities and age-and sex-matched healthy controls. We measured levels of IL-6, IL-1β, TNF-α, and IFN-γ in serum samples of HIP at the beginning and at month 6 of ART and in controls. Results: The mean age of the study subjects was 38.7 ±10.3 years, with men making up 86.7% of the study subjects (n=26). IL-6, IL-1β, and TNF-α levels were significantly higher in both ART-naive (p<0.001, p=0.002, p=0.001) and ART-experienced HIP (p<0.001) than controls. The IFN-γ level was lower in both ART-naive and ART-experienced HIP compared to controls (p=0.082 and p=0.002). There was a positive correlation between the CD4+T cell count and serum concentration of IFN- γ(r=0.320, p<0.05). While the serum IFN-γ concentration showed a negative correlation with the HIVRNA level(r=-0.412, p<0.001), the serum IL-1β, IL-6, and TNF-α concentrations showed a positive correlation with the HIV-RNA level (r=0.349, p<0.001; r:0.54, p<0.001; r:0.438, p<0.00). Conclusions: Although serum concentrations of IL-6, IL-1β and TNF-α showed a significant decrease after ART, they were still significantly higher than the controls. IFN-γ responded differently to ART compared to the other cytokines, indicating that it may play a distinct and important role in the pathogenesis of HIV infection.

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Batf3-Dependent Dendritic Cells Promote Optimal CD8 T Cell Responses against Respiratory Poxvirus Infection

Journal of Virology ◽

10.1128/jvi.00495-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 9

Author(s):

Pritesh Desai ◽

Vikas Tahiliani ◽

Georges Abboud ◽

Jessica Stanfield ◽

Shahram Salek-Ardakani

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Vaccinia Virus ◽

Respiratory Infection ◽

Host Resistance ◽

T Cell Responses ◽

Cell Responses ◽

Ifn Γ ◽

The Impact

ABSTRACTRespiratory infection with vaccinia virus (VacV) elicits robust CD8+T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8+effector T cell responses remains poorly defined. We used Batf3−/−mice to investigate the impact of CD103+and CD8α+dendritic cell (DC) deficiency on anti-VacV CD8+T cell responses. We found that Batf3−/−mice were more susceptible to VacV infection, exhibiting profound weight loss, which correlated with impaired accumulation of gamma interferon (IFN-γ)-producing CD8+T cells in the lungs. This was largely due to defective priming since early in the response, antigen-specific CD8+T cells in the draining lymph nodes of Batf3−/−mice expressed significantly reduced levels of Ki67, CD25, and T-bet. These results underscore a specific role for Batf3-dependent DCs in regulating priming and expansion of effector CD8+T cells necessary for host resistance against acute respiratory VacV infection.IMPORTANCEDuring respiratory infection with vaccinia virus (VacV), a member ofPoxviridaefamily, CD8+T cells play important role in resolving the primary infection. Effector CD8+T cells clear the virus by accumulating in the infected lungs in large numbers and secreting molecules such as IFN-γ that kill virally infected cells. However, precise cell types that regulate the generation of effector CD8+T cells in the lungs are not well defined. Dendritic cells (DCs) are a heterogeneous population of immune cells that are recognized as key initiators and regulators of T-cell-mediated immunity. In this study, we reveal that a specific subset of DCs that are dependent on the transcription factor Batf3 for their development regulate the magnitude of CD8+T cell effector responses in the lungs, thereby providing protection during pulmonary VacV infection.

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CD4 T Cell Antigens from Staphylococcus aureus Newman Strain Identified following Immunization with Heat-Killed Bacteria

Clinical and Vaccine Immunology ◽

10.1128/cvi.05642-11 ◽

2012 ◽

Vol 19 (4) ◽

pp. 477-489 ◽

Cited By ~ 9

Author(s):

Paulraj K. Lawrence ◽

Bachra Rokbi ◽

Nadège Arnaud-Barbe ◽

Eric L. Sutten ◽

Junzo Norimine ◽

...

Keyword(s):

Staphylococcus Aureus ◽

T Cell ◽

Reverse Genetics ◽

Vaccine Development ◽

Protein A ◽

Cd4 T Cell ◽

Content Type ◽

Intramammary Infections ◽

T Cell Antigens ◽

Ifn Γ

ABSTRACTStaphylococcus aureusis a commensal bacterium associated with the skin and mucosal surfaces of humans and animals that can also cause chronic infection. The emergence of antibiotic-resistant strains such as methicillin-resistantS. aureus(MRSA) and strains causing chronic intramammary infections (IMI) in cows results in severe human and livestock infections. Conventional approaches to vaccine development have yielded only a few noneffective vaccines against MRSA or IMI strains, so there is a need for improved vaccine development. CD4 T lymphocytes are required for promoting gamma interferon (IFN-γ) mediated immunoglobulin isotype switching in B lymphocytes to produce high-affinity IgG antibodies and IFN-γ-mediated phagocyte activation for an effective resolution of bacterial infection. However, the lack of known CD4 T cell antigens fromS. aureushas made it difficult to design effective vaccines. The goal of this study was to identifyS. aureusproteins recognized by immune CD4 T cells. Using a reverse genetics approach, 43 antigens were selected from theS. aureusNewman strain. These included lipoproteins, proteases, transcription regulators, an alkaline shock protein, conserved-domain proteins, hemolysins, fibrinogen-binding protein, staphylokinase, exotoxin, enterotoxin, sortase, and protein A. Screening of expressed proteins for recall T cell responses in outbred, immune calves identified 13 proteins that share over 80% sequence identity among MRSA or IMI strains. These may be useful for inclusion in a broadly protective multiantigen vaccine against MRSA or IMI.

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Tachyzoite-specific isoform of Toxoplasma gondii lactate dehydrogenase is the target antigen of a murine CD4+ T-cell clone

Microbes and Infection ◽

10.1016/s1286-4579(01)01434-4 ◽

2001 ◽

Vol 3 (10) ◽

pp. 779-787 ◽

Cited By ~ 13

Author(s):

Gaby Reichmann ◽

Henryka Długońska ◽

Ela Hiszczyńska-Sawicka ◽

Hans-Georg Fischer

Keyword(s):

Lactate Dehydrogenase ◽

T Cell ◽

Toxoplasma Gondii ◽

Cell Clone ◽

Cd4 T Cell ◽

Target Antigen ◽

T Cell Clone

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An Adaptive Chlamydia trachomatis-Specific IFN-γ-Producing CD4+ T Cell Response Is Associated With Protection Against Chlamydia Reinfection in Women

Frontiers in Immunology ◽

10.3389/fimmu.2018.01981 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 11

Author(s):

Rakesh K. Bakshi ◽

Kanupriya Gupta ◽

Stephen J. Jordan ◽

Xiaofei Chi ◽

Shelly Y. Lensing ◽

...

Keyword(s):

T Cell ◽

Chlamydia Trachomatis ◽

Cell Response ◽

T Cell Response ◽

Cd4 T Cell ◽

Ifn Γ

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Identification of Rotavirus VP6-Specific CD4+ T Cell Epitopes in a G1P[8] Human Rotavirus-Infected Rhesus Macaque

Virology Research and Treatment ◽

10.4137/vrt.s563 ◽

2008 ◽

Vol 1 ◽

pp. VRT.S563 ◽

Cited By ~ 1

Author(s):

Wei Zhao ◽

Bapi Pahar ◽

Karol Sestak

Keyword(s):

T Cell ◽

Rhesus Macaques ◽

Immunoglobulin A ◽

Cd4 T Cell ◽

T Cell Epitopes ◽

Primate Model ◽

Human Rotavirus ◽

Ifn Γ ◽

Rotavirus Vp6

A non-human primate model was used to evaluate its potential for identification of rotavirus viral protein 6 (VP6) CD4+ T cell epitopes. Four juvenile rhesus macaques were inoculated with a mixed inoculum (G1P[8] and G9P[8]) of human rotaviruses. Infection accompanied by G1P[8] shedding was achieved in the two macaques that had no rotavirus immunoglobulin A (IgA) in plasma. To measure the interferon gamma (IFN-γ) and tumor necrosis factor (TNF) anti-viral cytokines produced by peripheral CD4+ cells that recognize VP6 epitopes, whole blood cells from one infected macaque were stimulated in vitro with VP6 peptides. Stimulation with peptide pools derived from the simian rotavirus VP6161–395 region revealed reactivity of CD4+ T cells with the VP6281–331 domain. A VP6301–315 region was identified as the epitope responsible for IFN-γ production while a broader VP6293–327 domain was linked to TNF production. These results suggest that human rotavirus-infected macaques can be used for identification of additional epitopes and domains to address specific questions related to the development of pediatric vaccines.

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