CD8 T Cells Producing IL-17 and IFN-γ Initiate the Innate Immune Response Required for Responses to Antigen Skin Challenge

Interferon (IFN)-γ plays an important role in the innate immune response against intracellular bacterial pathogens. It is commonly thought that natural killer cells are the primary source of this cytokine that is involved in activating antibacterial effects in infected cells and polarizing CD4+ T cells toward the Th1 subset. However, here we show that both effector and memory CD8+ T cells have the potential to secrete IFN-γ in response to interleukin (IL)-12 and IL-18 in the absence of cognate antigen. We demonstrate that memory CD8+ T cells specific for the ovalbumin protein secrete IFN-γ rapidly after infection with wild-type Listeria monocytogenes (LM). Furthermore, small numbers of ovalbumin-specific, memory CD8+ T cells can reduce spleen and liver bacterial counts in IFN-γ–deficient mice 3 d after LM infection. Up-regulation of the receptors for IL-12 and IL-18 provides a mechanism for the ability of memory CD8+ T cells to respond in this antigen nonspecific manner. Thus, CD8+ T cells play an important role in the innate immune response against intracellular pathogens by rapidly secreting IFN-γ in response to IL-12 and IL-18.

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Preliminary effects on the innate immune system with the combination of cetuximab and durvalumab in metastatic/ relapsed head and neck squamous cell carcinoma in a phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14273 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14273-e14273

Author(s):

Shuchi Gulati ◽

Rachel Vachon ◽

Shireen Desai ◽

Aubrey Steele ◽

Sarah Palackdharry ◽

...

Keyword(s):

Clinical Trial ◽

Immune Response ◽

Squamous Cell Carcinoma ◽

T Cells ◽

Innate Immune Response ◽

Cd8 T Cells ◽

Nk Cell ◽

Post Treatment ◽

Innate Immune ◽

Adaptive Immune

e14273 Background: Cetuximab is a recombinant chimeric monoclonal IgG1 antibody which binds specifically to the epidermal growth factor receptor (EGFR) and stimulates an innate immune response by promoting natural killer (NK) cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab is approved as a single agent in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC). PD-1 check-point inhibitors which release the inhibition of the adaptive immune response, are also approved as single agents in this setting. However the response rates with these drugs, when used individually range from 10-20%. We hypothesized that adding a PD-L1 inhibitor, durvalumab to cetuximab would cause anti-tumor synergy by activating the innate as well as adaptive immune systems without compromising safety in this phase-2 trial in R/M HNSCC patients who have progressed on platinum based therapy. Methods: Blood samples were collected from the first six enrolled patients prior to starting treatment and 4 weeks after the first combined dose of cetuximab and durvalumab. PBMCs were isolated, stained with a live/dead stain as well as CD3, CD4, CD8, CD56, CD16 and NK2GD (natural killer group 2 member D activation receptor) antibodies and analyzed by flow cytometry. Cytokine levels in plasma were measured using standardized ELISA assay kits. Results: Compared to pre-treatment levels, post-treatment samples showed an increase in activated cytokine producing NK cells (CD56bright/CD16-) in all but one patient. Activated cytotoxic NK cell subpopulations (CD56dim/CD16+) showed variable results post-treatment. CD8+ T cells were similar pre and post-treatment in 5 patients. TGF-b levels increased in 5 patients and decreased in 1 patient post-treatment. Interestingly, the patient with decreased TGF-b levels post-treatment had an almost doubling of CD8+ T-cells and an increase in activated cytokine producing NK cells (CD56bright/CD16-). Conclusions: The clinical trial is ongoing and therefore, comparison to clinical response has not yet been analyzed. However, these findings support the combination of cetuximab and durvalumab in R/M HNSCC given the activation of an NK-cell mediated innate immune response in these patient samples. Clinical trial information: NCT03691714.

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CD8 + T Cells from Human Neonates Are Biased toward an Innate Immune Response

Cell Reports ◽

10.1016/j.celrep.2016.10.056 ◽

2016 ◽

Vol 17 (8) ◽

pp. 2151-2160 ◽

Cited By ~ 22

Author(s):

Ariel O. Galindo-Albarrán ◽

Oscar H. López-Portales ◽

Darely Y. Gutiérrez-Reyna ◽

Otoniel Rodríguez-Jorge ◽

José Antonio Sánchez-Villanueva ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Innate Immune Response ◽

Cd8 T Cells ◽

Innate Immune ◽

Human Neonates

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IMMU-15. PD-1 BLOCKADE ACTIVATES CD4 T CELLS AND THE INNATE IMMUNE RESPONSE FOR GLIOBLASTOMA ERADICATION

Neuro-Oncology ◽

10.1093/neuonc/nox168.474 ◽

2017 ◽

Vol 19 (suppl_6) ◽

pp. vi115-vi116 ◽

Cited By ~ 1

Author(s):

Sarah R Klein ◽

Maria Carmela Speranza ◽

Prafulla C Gokhale ◽

Margaret K Wilkens ◽

Kristen L Jones ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Innate Immune Response ◽

Cd4 T Cells ◽

Innate Immune

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The effect of Kefir on The Immune Response of Healthy Volunteers In Vitro

Journal of Agromedicine and Medical Sciences ◽

10.19184/ams.v3i2.5067 ◽

2017 ◽

Vol 3 (2) ◽

pp. 28

Author(s):

Desie Dwi Wisudanti

Keyword(s):

Immune Response ◽

T Cells ◽

Immune Responses ◽

Healthy Volunteers ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Fermented Milk ◽

Bioactive Components ◽

Ifn Γ

Kefir is a functional foodstuff of probiotics, made from fermented milk with kefir grains containing various types of beneficial bacteria and yeast. There have been many studies on the effects of oral kefir on the immune system, but few studies have shown the effect of bioactive components from kefir (peptides and exopolysaccharides/ kefiran), on immune responses. The purpose of this study was to prove the effect of kefir supernatant from milk goat on healthy immune volunteer response in vitro. The study was conducted on 15 healthy volunteers, then isolated PBMC from whole blood, then divided into 5 groups (K-, P1, P2, P3 and P4) before culture was done for 4 days. The harvested cells from culture were examined for the percentage of CD4+ T cells, CD8+ T cells, IFN-γ, IL-4 using flowsitometry and IL-2 levels, IL-10 using the ELISA method. The results obtained that kefir do not affect the percentage of CD4+ T cells and CD8+ T cells. The higher the concentration of kefir given, the higher levels of secreted IFN- γ and IL-4, but a decrease in IL-2 levels. Significant enhancement occurred at levels of IL-10 culture PBMC given kefir with various concentrations (p <0.01), especially at concentrations of 1%. These results also show the important effects of kefir bioactive components on immune responses. The conclusion of this study is that kefir can improve the immune response, through stimulation of IL-10 secretion in vitro.

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Early Response of CD8+ T Cells in COVID-19 Patients

Journal of Personalized Medicine ◽

10.3390/jpm11121291 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1291

Author(s):

Deni Ramljak ◽

Martina Vukoja ◽

Marina Curlin ◽

Katarina Vukojevic ◽

Maja Barbaric ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

T Cells ◽

Mrna Expression ◽

Cd8 T Cells ◽

Expression Profiles ◽

Expression Patterns ◽

Effector Memory ◽

Healthy Controls ◽

Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

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Longitudinal single-cell immune profiling revealed distinct innate immune response in asymptomatic COVID-19 patients

10.1101/2020.09.02.276865 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xiang-Na Zhao ◽

Yue You ◽

Guo-Lin Wang ◽

Hui-Xia Gao ◽

Xiao-Ming Cui ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Single Cell ◽

Innate Immune Response ◽

Clonal Expansion ◽

Innate Immune ◽

Type I ◽

Severe Condition ◽

Asymptomatic Patients

SUMMARYRecent studies have characterized the single-cell immune landscape of host immune response of coronavirus disease 2019 (COVID-19), specifically focus on the severe condition. However, the immune response in mild or even asymptomatic patients remains unclear. Here, we performed longitudinal single-cell transcriptome sequencing and T cell/B cell receptor sequencing on 3 healthy donors and 10 COVID-19 patients with asymptomatic, moderate, and severe conditions. We found asymptomatic patients displayed distinct innate immune responses, including increased CD56briCD16− NK subset, which was nearly missing in severe condition and enrichment of a new Th2-like cell type/state expressing a ciliated cell marker. Unlike that in moderate condition, asymptomatic patients lacked clonal expansion of effector CD8+ T cells but had a robust effector CD4+ T cell clonal expansion, coincide with previously detected SARS-CoV-2-reactive CD4+ T cells in unexposed individuals. Moreover, NK and effector T cells in asymptomatic patients have upregulated cytokine related genes, such as IFNG and XCL2. Our data suggest early innate immune response and type I immunity may contribute to the asymptomatic phenotype in COVID-19 disease, which could in turn deepen our understanding of severe COVID-19 and guide early prediction and therapeutics.

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Innate Immune Response against HPV: Possible Crosstalking with Endocervical γδ T Cells

Journal of Reproductive Immunology ◽

10.1016/j.jri.2021.103435 ◽

2021 ◽

pp. 103435

Author(s):

Selen Dogan ◽

Ender Terzioglu ◽

Selda Ucar

Keyword(s):

Immune Response ◽

T Cells ◽

Innate Immune Response ◽

Γδ T Cells ◽

Innate Immune

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The Exopolysaccharide of Lactobacillus fermentum UCO-979C Is Partially Involved in Its Immunomodulatory Effect and Its Ability to Improve the Resistance against Helicobacter pylori Infection

Microorganisms ◽

10.3390/microorganisms8040479 ◽

2020 ◽

Vol 8 (4) ◽

pp. 479

Author(s):

Valeria Garcia-Castillo ◽

Guillermo Marcial ◽

Leonardo Albarracín ◽

Mikado Tomokiyo ◽

Patricia Clua ◽

...

Keyword(s):

Immune Response ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Innate Immune Response ◽

Innate Immune ◽

Helicobacter Pylori Infection ◽

Beneficial Effects ◽

Ifn Γ ◽

H Pylori

Lactobacillus fermentum UCO-979C (Lf979C) beneficially modulates the cytokine response of gastric epithelial cells and macrophages after Helicobacter pylori infection in vitro. Nevertheless, no in vivo studies were performed with this strain to confirm its beneficial immunomodulatory effects. This work evaluated whether Lf979C improves protection against H. pylori infection in mice by modulating the innate immune response. In addition, we evaluated whether its exopolysaccharide (EPS) was involved in its beneficial effects. Lf979C significantly reduced TNF-α, IL-8, and MCP-1 and augmented IFN-γ and IL-10 in the gastric mucosa of H. pylori-infected mice. The differential cytokine profile induced by Lf979C in H. pylori-infected mice correlated with an improved reduction in the pathogen gastric colonization and protection against inflammatory damage. The purified EPS of Lf979C reduced IL-8 and enhanced IL-10 levels in the gastric mucosa of infected mice, while no effect was observed for IFN-γ. This work demonstrates for the first time the in vivo ability of Lf979C to increase resistance against H. pylori infection by modulating the gastric innate immune response. In addition, we advanced knowledge of the mechanisms involved in the beneficial effects of Lf979C by demonstrating that its EPS is partially responsible for its immunomodulatory effect.

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Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Journal of Virology ◽

10.1128/jvi.01272-16 ◽

2016 ◽

Vol 90 (23) ◽

pp. 10823-10843 ◽

Cited By ~ 9

Author(s):

Nicole Arnold ◽

Thomas Girke ◽

Suhas Sureshchandra ◽

Ilhem Messaoudi

Keyword(s):

Gene Expression ◽

Immune Response ◽

T Cells ◽

Virus Infection ◽

Innate Immune Response ◽

Rhesus Macaques ◽

Innate Immune ◽

Sensory Ganglia ◽

Simian Varicella Virus ◽

Varicella Virus

ABSTRACTPrimary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression.IMPORTANCEMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection.

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