scholarly journals Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection

2018 ◽  
Vol 92 (10) ◽  
pp. e00014-18 ◽  
Author(s):  
Renan Aguilar-Valenzuela ◽  
Jason Netland ◽  
Young-Jin Seo ◽  
Michael J. Bevan ◽  
Arash Grakoui ◽  
...  
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
T Cell ◽  
Immunodominant Epitope ◽  
West Nile ◽  
Cell Responses ◽  
Immunological Mechanisms ◽  
The Brain ◽  
Ns4b Protein

ABSTRACT The mouse model of West Nile virus (WNV), which is a leading cause of mosquito-borne encephalitis worldwide, has provided fundamental insights into the host and viral factors that regulate viral pathogenesis and infection outcome. In particular, CD8+ T cells are critical for controlling WNV replication and promoting protection against infection. Here, we present the characterization of a T cell receptor (TCR)-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein (here referred to as transgenic WNV-I mice). Using an adoptive-transfer model, we found that WNV-I CD8+ T cells behave similarly to endogenous CD8+ T cell responses, with an expansion phase in the periphery beginning around day 7 postinfection (p.i.) followed by a contraction phase through day 15 p.i. Through the use of in vivo intravascular immune cell staining, we determined the kinetics, expansion, and differentiation into effector and memory subsets of WNV-I CD8+ T cells within the spleen and brain. We found that red-pulp WNV-I CD8+ T cells were more effector-like than white-pulp WNV-I CD8+ T cells, which displayed increased differentiation into memory precursor cells. Within the central nervous system (CNS), we found that WNV-I CD8+ T cells were polyfunctional (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]), displayed tissue-resident characteristics (CD69+ and CD103+), persisted in the brain through day 15 p.i., and reduced the viral burden within the brain. The use of these TCR-transgenic WNV-I mice provides a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection. IMPORTANCE West Nile Virus (WNV) is the leading cause of mosquito-borne encephalitis worldwide. There are currently no approved therapeutics or vaccines for use in humans to treat or prevent WNV infection. CD8+ T cells are critical for controlling WNV replication and protecting against infection. Here, we present a comprehensive characterization of a novel TCR-transgenic mouse with specificity for the immunodominant epitope in the WNV NS4B protein. In this study, we determine the kinetics, proliferation, differentiation into effector and memory subsets, homing, and clearance of WNV in the CNS. Our findings provide a new resource to dissect the immunological mechanisms of CD8+ T cell-mediated protection during WNV infection.

scholarly journals MAVS Expressed by Hematopoietic Cells Is Critical for Control of West Nile Virus Infection and Pathogenesis

2016 ◽  
Vol 90 (16) ◽  
pp. 7098-7108 ◽  
Author(s):  
Jincun Zhao ◽  
Rahul Vijay ◽  
Jingxian Zhao ◽  
Michael Gale ◽  
Michael S. Diamond ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
West Nile Virus ◽  
Hematopoietic Cells ◽  
The United States ◽  
Innate Immune ◽  
Target Cells ◽  
West Nile ◽  
Adaptor Molecule ◽  
The Brain

ABSTRACTWest Nile virus (WNV) is the most important cause of epidemic encephalitis in North America. Innate immune responses, which are critical for control of WNV infection, are initiated by signaling through pathogen recognition receptors, RIG-I and MDA5, and their downstream adaptor molecule, MAVS. Here, we show that a deficiency of MAVS in hematopoietic cells resulted in increased mortality and delayed WNV clearance from the brain. InMavs−/−mice, a dysregulated immune response was detected, characterized by a massive influx of macrophages and virus-specific T cells into the infected brain. These T cells were polyfunctional and lysed peptide-pulsed target cellsin vitro. However, virus-specific T cells in the brains of infectedMavs−/−mice exhibited lower functional avidity than those in wild-type animals, and even virus-specific memory T cells generated by prior immunization could not protectMavs−/−mice from WNV-induced lethal disease. Concomitant with ineffective virus clearance, macrophage numbers were increased in theMavs−/−brain, and both macrophages and microglia exhibited an activated phenotype. Microarray analyses of leukocytes in the infectedMavs−/−brain showed a preferential expression of genes associated with activation and inflammation. Together, these results demonstrate a critical role for MAVS in hematopoietic cells in augmenting the kinetics of WNV clearance and thereby preventing a dysregulated and pathogenic immune response.IMPORTANCEWest Nile virus (WNV) is the most important cause of mosquito-transmitted encephalitis in the United States. The innate immune response is known to be critical for protection in infected mice. Here, we show that expression of MAVS, a key adaptor molecule in the RIG-I-like receptor RNA-sensing pathway, in hematopoietic cells is critical for protection from lethal WNV infection. In the absence of MAVS, there is a massive infiltration of myeloid cells and virus-specific T cells into the brain and overexuberant production of proinflammatory cytokines. These results demonstrate the important role that MAVS expression in hematopoietic cells has in regulating the inflammatory response in the WNV-infected brain.

scholarly journals Key role of T cell defects in age-related vulnerability to West Nile virus

2009 ◽  
Vol 206 (12) ◽  
pp. 2735-2745 ◽  
Author(s):  
James D. Brien ◽  
Jennifer L. Uhrlaub ◽  
Alec Hirsch ◽  
Clayton A. Wiley ◽  
Janko Nikolich-Žugich
Keyword(s):  
T Cells ◽  
West Nile Virus ◽  
T Cell ◽  
Cd8 T Cells ◽  
The Elderly ◽  
T Cell Response ◽  
West Nile ◽  
Immunodeficient Mice ◽  
Age Related ◽  
Cell Immunity

West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40–50× more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity. In contrast, at the peak of the response, old and adult T cells exhibited superimposable peptide sensitivity. Most importantly, although the adult CD4 or CD8 T cells readily protected immunodeficient mice upon adoptive transfer, old T cells of either subset were unable to provide WNV-specific protection. Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12× fewer total effector CD8 T cells compared with adult mice at the peak of brain infection. These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly.

scholarly journals Comprehensive Analysis of West Nile Virus–Specific T Cell Responses in Humans

2008 ◽  
Vol 197 (9) ◽  
pp. 1296-1306 ◽  
Author(s):  
Marion C. Lanteri ◽  
John W. Heitman ◽  
Rachel E. Owen ◽  
Thomas Busch ◽  
Nelly Gefter ◽  
...  
Keyword(s):  
West Nile Virus ◽  
T Cell ◽  
T Cell Responses ◽  
Comprehensive Analysis ◽  
West Nile ◽  
Cell Responses

scholarly journals IL-10 and ICOS differentially regulate T cell responses in the brain during chronicToxoplasma gondiiinfection

2018 ◽  
Author(s):  
Carleigh A. O’Brien ◽  
Samantha J. Batista ◽  
Katherine M. Still ◽  
Tajie H. Harris
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Chronic Phase ◽  
T Cell Responses ◽  
T Cell Response ◽  
Neutrophil Recruitment ◽  
Cns Infection ◽  
Cell Responses ◽  
The Brain

AbstractControl of chronic CNS infection with the parasiteToxoplasma gondiirequires an ongoing T cell response in the brain. Immunosuppressive cytokines are also important for preventing lethal immunopathology during chronic infection. To explore the loss of suppressive cytokine exclusively during the chronic phase of infection we blocked IL-10 receptor (IL-10R). Blockade was associated with widespread changes in the inflammatory response, including increased antigen presenting cell (APC) activation, expansion of CD4+ T cells, and increased neutrophil recruitment to the brain, consistent with previous reports. We then sought to identify regulatory mechanisms contributing to IL-10 production, focusing on ICOS (inducible T cell costimulator), a molecule that promotes IL-10 production in many systems. Unexpectedly, ICOS-ligand (ICOSL) blockade led to a local expansion of effector T cells in the inflamed brain without affecting IL-10 production or APC activation. Instead, we found that ICOSL blockade led to changes in T cells associated with their proliferation and survival. Specifically, we observed increased expression of IL-2 associated signaling molecules, including CD25, STAT5 phosphorylation, Ki67, and Bcl-2 in T cells in the brain. Interestingly, increases in CD25 and Bcl-2 were not observed following IL-10R blockade. Also unlike IL-10R blockade, ICOSL blockade led to an expansion of both CD8+ and CD4+ T cells in the brain, with no expansion of peripheral T cell populations or neutrophil recruitment to the brain Overall, these results suggest that IL-10 and ICOS differentially regulate T cell responses in the brain during chronicT. gondiiinfection.

scholarly journals Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice

2015 ◽  
Vol 90 (3) ◽  
pp. 1333-1344 ◽  
Author(s):  
Guorui Xie ◽  
Huanle Luo ◽  
Lan Pang ◽  
Bi-hung Peng ◽  
Evandro Winkelmann ◽  
...  
Keyword(s):  
West Nile Virus ◽  
T Cell ◽  
Protective Efficacy ◽  
T Cell Responses ◽  
The Elderly ◽  
Γδ T Cell ◽  
West Nile ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Old Mice

ABSTRACTThe elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), a mosquito-borne flavivirus, has induced severe neurological symptoms, mostly in the elderly population. No vaccines are available for human use. Recent work showed that an attenuated WNV, a nonstructural (NS) 4B-P38G mutant, induced no lethality but strong immune responses in young (6- to 10-week-old) mice. While studying protective efficacy, we found unexpectedly that old (21- to 22-month) mice were susceptible to WNV NS4B-P38G mutant infection but were protected from subsequent lethal wild-type WNV challenge. Compared to responses in young mice, the NS4B-P38G mutant triggered higher inflammatory cytokine and interleukin-10 (IL-10) production, a delayed γδ T cell expansion, and lower antibody and WNV-specific T cell responses in old mice. Toll-like receptor 7 (TLR7) is expressed on multiple types of cells. Impaired TLR7 signaling in old mice led to dendritic cell (DC) antigen-presenting function compromise and a reduced γδ T cell and regulatory T cell (Treg) expansion during NS4B-P38G mutant infection. R848, a TLR7 agonist, decreased host vulnerability in NS4B-P38G-infected old mice by enhancing γδ T cell and Treg expansion and the antigen-presenting capacity of DCs, thereby promoting T cell responses. In summary, our results suggest that dysregulation of TLR7 partially contributes to impaired innate and adaptive T cell responses and an enhanced vulnerability in old mice during WNV NS4B-P38G mutant infection. R848 increases the safety and efficacy during immunization of old mice with the WNV NS4B-P38G mutant.IMPORTANCEThe elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), an emerging mosquito-borne flavivirus, has induced severe neurological symptoms more frequently in the elderly population. No vaccines are available for human use. Here, we used an aged mouse model to investigate the protective efficacy of an attenuated WNV, the nonstructural 4B-P38G mutant, which was previously shown to induce no lethality but strong immune responses in young adult mice. Studies that contribute to a mechanistic understanding of immune defects in the elderly will allow the development of strategies to improve responses to infectious diseases and to increase vaccine efficacy and safety in aging individuals.

scholarly journals Functional analysis of peripheral and intratumoral neoantigen-specific TCRs identified in a patient with melanoma

2021 ◽  
Vol 9 (9) ◽  
pp. e002754
Author(s):  
Eva Bräunlein ◽  
Gaia Lupoli ◽  
Franziska Füchsl ◽  
Esam T Abualrous ◽  
Niklas de Andrade Krätzig ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
T Cell Responses ◽  
Functional Avidity ◽  
Cell Responses

BackgroundNeoantigens derived from somatic mutations correlate with therapeutic responses mediated by treatment with immune checkpoint inhibitors. Neoantigens are therefore highly attractive targets for the development of therapeutic approaches in personalized medicine, although many aspects of their quality and associated immune responses are not yet well understood. In a case study of metastatic malignant melanoma, we aimed to perform an in-depth characterization of neoantigens and respective T-cell responses in the context of immune checkpoint modulation.MethodsThree neoantigens, which we identified either by immunopeptidomics or in silico prediction, were investigated using binding affinity analyses and structural simulations. We isolated seven T-cell receptors (TCRs) from the patient’s immune repertoire recognizing these antigens. TCRs were compared in vitro by multiparametric analyses including functional avidity, multicytokine secretion, and cross-reactivity screenings. A xenograft mouse model served to study in vivo functionality of selected TCRs. We investigated the patient’s TCR repertoire in blood and different tumor-related tissues over 3 years using TCR beta deep sequencing.ResultsSelected mutated peptide ligands with proven immunogenicity showed similar binding affinities to the human leukocyte antigen complex and comparable disparity to their wild-type counterparts in molecular dynamic simulations. Nevertheless, isolated TCRs recognizing these antigens demonstrated distinct patterns in functionality and frequency. TCRs with lower functional avidity showed at least equal antitumor immune responses in vivo. Moreover, they occurred at high frequencies and particularly demonstrated long-term persistence within tumor tissues, lymph nodes and various blood samples associated with a reduced activation pattern on primary in vitro stimulation.ConclusionsWe performed a so far unique fine characterization of neoantigen-specific T-cell responses revealing defined reactivity patterns of neoantigen-specific TCRs. Our data highlight qualitative differences of these TCRs associated with function and longevity of respective T cells. Such features need to be considered for further optimization of neoantigen targeting including adoptive T-cell therapies using TCR-transgenic T cells.

scholarly journals Characterization of Recombinant Respiratory Syncytial Viruses with the Region Responsible for Type 2 T-Cell Responses and Pulmonary Eosinophilia Deleted from the Attachment (G) Protein

2004 ◽  
Vol 78 (16) ◽  
pp. 8446-8454 ◽  
Author(s):  
Matthew B. Elliott ◽  
Karin S. Pryharski ◽  
Qingzhong Yu ◽  
L. A. Boutilier ◽  
N. Campeol ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
T Cell ◽  
G Protein ◽  
Inbred Mice ◽  
T Cell Responses ◽  
Pulmonary Eosinophilia ◽  
Cell Responses

ABSTRACT It is essential that preventative vaccines for respiratory syncytial virus (RSV) elicit balanced T-cell responses. Immune responses dominated by type 2 T cells against RSV antigens are believed to cause exaggerated respiratory tract disease and may also contribute to unwanted inflammation in the airways that predisposes infants to wheeze through adolescence. Here we report on the construction and characterization of recombinant RSV (rRSV) strains with amino acids 151 to 221 or 178 to 219 of the attachment (G) glycoprotein deleted (rA2cpΔG150-222 or rA2cpΔG177-220, respectively). The central ectodomain was chosen for modification because a peptide spanning amino acids 149 to 200 of G protein has recently been shown to prime several strains of naïve inbred mice for polarized type 2 T-cell responses, and peripheral blood T cells from most human donors recognize epitopes within this region. Quantitative PCR demonstrated that synthesis of nascent rRSV genomes in human lung epithelial cell lines was similar to that for the parent virus (cp-RSV). Plaque assays further indicated that rRSV replication was not sensitive to 37°C, but pinpoint morphology was observed at 39°C. Both rRSV strains replicated in the respiratory tracts of BALB/c mice and elicited serum neutralization and anti-F-protein immunoglobulin G titers that were equivalent to those elicited by cp-RSV and contributed to a 3.9-log10-unit reduction in RSV A2 levels 4 days after challenge. Importantly, pulmonary eosinophilia was significantly diminished in BALB/c mice primed with native G protein and challenged with either rA2cpΔG150-222 or rA2cpΔG177-220. These findings are important for the development of attenuated RSV vaccines.

scholarly journals Characterization of CD8+T-Cell Responses in the Peripheral Blood and Skin Injection Sites of Melanoma Patients Treated with mRNA Electroporated Autologous Dendritic Cells (TriMixDC-MEL)

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Daphné Benteyn ◽  
An M. T. Van Nuffel ◽  
Sofie Wilgenhof ◽  
Jurgen Corthals ◽  
Carlo Heirman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Antigen Specificity ◽  
Cell Responses ◽  
Melanoma Patients

Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to migrate to both the skin and internal organs. We monitored the presence of TAA-specific CD8+T cells infiltrating the skin at sites of intradermal TriMixDC-MEL injection (SKILs) and within the circulation of melanoma patients treated in two clinical trials. In 10 out of fourteen (71%) patients screened, CD8+T cells recognizing any of the four TAA presented by TriMixDC-MEL cellular vaccine were found in both compartments. In total, 30 TAA-specific T-cell responses were detected among the SKILs and 29 among peripheral blood T cells, of which 24 in common. A detailed characterization of the antigen specificity of CD8+T-cell populations in four patients indicates that the majority of the epitopes detected were only recognized by CD8+T cells derived from either skin biopsies or peripheral blood, indicating that some compartmentalization occurs after TriMix-DC therapy. To conclude, functional TAA-specific CD8+T cells distribute both to the skin and peripheral blood of patients after TriMixDC-MEL therapy.

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