scholarly journals Frequent Recurrences of Genital Herpes Are Associated with Enhanced Systemic HSV-Specific T Cell Response

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Michal Holub ◽  
Alžběta Stráníková ◽  
Pavel Chalupa ◽  
Simona Arientová ◽  
Kateřina Roubalová ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Genital Herpes ◽  
Cd8 T Cells ◽  
High Frequency ◽  
Low Frequency ◽  
T Cell Responses ◽  
Healthy Controls ◽  
Cell Responses ◽  
Hla Dr

Objectives. Genital herpes simplex virus (HSV) infection is controlled by HSV-specific T cells in the genital tract, and the role of systemic T cell responses is not fully understood. Thus, we analysed T cell responses in patients with recurrent genital herpes (GH). Methods. T cell responses to HSV-1 and HSV-2 native antigens and the expression of HLA-DR and CD38 molecules on circulating CD8+ T cells were analysed in adults with high frequency of GH recurrences (19 patients) and low frequency of GH recurrences (7 patients) and 12 HSV-2 seronegative healthy controls. The study utilized the interferon-γ Elispot assay for measurement of spot-forming cells (SFC) after ex vivo stimulation with HSV antigens and flow cytometry for analysis of the expression of activation markers in unstimulated T cells. Results. The patients with high frequency of GH recurrences (mean number of recurrences of 13.3 per year) had significantly enhanced HSV-specific T cell responses than the HSV-2 seronegative healthy controls. Moreover, a trend of higher numbers of SFC was observed in these patients when compared with those with low frequency of GH recurrences (mean number of recurrences of 3.3 per year). Additionally, no differences in CD38 and HLA-DR expression on circulating CD8+ T cells were found among the study groups. Conclusions. Frequency of GH recurrences positively correlates with high numbers of systemic HSV-specific T cells.

The Mutated Region of Cytoplasmatic Nucleophosmine 1 (NPM1) Elicits Both CD4+ and CD8+ T Cell Responses

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2569-2569
Author(s):  
Jochen Greiner ◽  
Yoko Ono ◽  
Susanne Hofmann ◽  
Vanessa Schneider ◽  
Anita Schmitt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Healthy Volunteers ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Granzyme B ◽  
T Cell Responses ◽  
Interferon Γ ◽  
Cell Responses ◽  
Hla Dr

Abstract Abstract 2569 Introduction In AML, mutations in the nucleophosmin (NPM1) gene are one of the most frequent molecular alterations and predominantly occur in AML with normal cytogenetics. Patients with NPM1 mutation without FLT3-ITD mutation show a favourable prognosis of their disease. The functional role of mutated NPM1 for the improved clinical outcome is under evaluation. Immune responses might be involved in the clinical outcome of the disease. In this work, we demonstrate both CD4+ and CD8+ T cell responses against the mutated region of NPM1. Methods The entire amino acid sequences of the NPM1 wild type protein as well as of the mutated cytoplasmic NPM1 types A, B, C and D were screened for HLA-A*0201 binding T cell epitopes using the algorithms of the SYFPEITHI, the Rankpep and the HLA-Bind software programs. Ten peptides with most favourable characteristics were subjected to ELISpot analysis for interferon-γ and granzyme B in 22 healthy volunteers and 27 AML patients to test specific T cell responses of CD8+ T cells. Tetramer assays against the two most interesting epitopes have been performed and chromium release assays have been used to show the cytotoxicity of peptide-specific T cells to lyse T2 cells and leukemic blasts. Moreover, HLA-DR binding epitopes were screened in algorithmic analysis and HLA-DR*0701 binding peptides were exploited to stimulate CD4+ T cells. In the presence of overlapping peptide stimulated CD4+ T cells, NPM1-A specific CD8+ T cells revealed augmented interferon-γ and granzyme B secretion and up-regulation of intracellular interferon-γ. CD4+, CD4-CD8+, CD4-CD8- cell fractions were separated from PBMCs of HLA-A2+DR*0701+ healthy volunteers using a combination of CD4 and CD8 MicroBeads. Results Two epitopes (P3 and P9) derived from the NPM1-mutated protein showed specific T cell responses in healthy volunteers and AML patients. In NPM1-mutated AML patients 33% showed immune responses of CD8+ T cells against peptide P3 and 42% against peptide P9. Specific lysis was detected in chromium release assays NPM1 peptide-primed effector T cells generated from NPM1-mutated AML patients. Tetramer assays showed peptide-specific T cells. To obtain a robust and effective immune response against tumor cells, the activation of CD4 + helper T cells is crucial. Thus NPM1-peptide-A overlapping MHC class II epitopes were searched by primary structure analysis program. Based on plenary search, eight favourable overlapping peptides OL 1–8 were synthesized and exploited for CD4+ T cell stimulation. In granzyme B ELISPOT assay, OL8 co-pulsed NPM1-A CD8+ T cells indicated notable S.I., in contrast other OL1-7 disabled to increase granzyme B secretion. To ensure that Th1 cytokine secretion, under the condition of CD8+ and CD4+ T cells mixed culture, was resulted from NPM1-A CD8+ T cells but not HLA-DR epitope stimulated CD4+ T cells activation, HLA-A2 blocking effect was confirmed in ELISPOT assay. NPM1-A CD8+ T cells co-pulsed with OL6, 7 and 8 showed lesser interferon-γ secretion after HLA-A2 blocking antibody exposure as 73, 35 and 57%. Of note, 83–94% of granzyme B secretion levels were reduced by HLA-A2 blockade administration, and by which NPM1-A CD8+ T cells seemed to be the most probable IFN-gamma and granzyme B producers and CD4+ T cells to interfere with CD8+ T cells. Conclusion Taken together, mutated NPM1 is a promising target structure for specific immunotherapies in AML patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High-Frequency Alloreactive T Cells Augment Effector Function of Low-Frequency CD8+ T-Cell Responses Under CD28/CD154 Blockade

2010 ◽  
Vol 89 (10) ◽  
pp. 1208-1217 ◽  
Author(s):  
Tamara L. Floyd ◽  
Steven B. Orr ◽  
Shana M. Coley ◽  
Samantha S. Hanna ◽  
Maylene E. Wagener ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Frequency ◽  
Low Frequency ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Effector Function ◽  
Cell Responses ◽  
Alloreactive T Cells

758 Identification of tumor antigen-specific T cells in the peripheral blood of colorectal cancer patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A806-A806
Author(s):  
Emilie Picard ◽  
Alexandrine Martel ◽  
Alain Simard ◽  
Hoang-Thanh Le ◽  
Chris Verschoor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Healthy Controls ◽  
Ifn Gamma ◽  
Cell Responses ◽  
Healthy Control

BackgroundInteractions between the immune system and the tumor are now recognized as key determinants of clinical outcome in colorectal cancer (CRC). Immune landscapes have been extensively studied within resected primary tumors and immune markers, such as T cells, have been found to be associated with CRC patients‘ survival. Little is known about the immune profile of cells in peripheral blood. We hypothesize that the functional status of T cells, characterized by their response to CRC tumor-associated antigens (TAAs), can be monitored in the peripheral blood of patients and that they have prognostic relevance in CRC.MethodsIn vitro T cell responses to pools of overlapping peptides representing the TAAs MUC-1, hTERT, NY-ESO-1 and CEA were assessed by analyzing IFN-gamma and TNF-alpha production by CD8+ T cells using flow cytometry, in 5 stage II-III CRC patients just prior to surgical resection and 3 healthy age- and sex-matched controls.ResultsT cells responding to MUC-1, hTERT, NY-ESO-1 and CEA were present in 3, 3, 1 and 5 CRC patients, respectively, whereas only one response to TAAs (MUC-1) was found in one healthy control (figure 1). When TAA responses were pooled together, 83.3% of responders were patients (n=5) and 100% of non-responders were healthy controls (n=2).Abstract 758 Figure 1CRC TAA-specific CD8 T cell responses in CRC patieDot plot of one representative healthy control (#3) and one representative patient (#2) showing IFN-γ production by CD8 T cells in response to (A) MUC-1, hTERT, NY-ESO-1 and CEA stimulations or without any restimulation (negative control) and (B) positive controls (CEF and PMA/ionomycin). Percentages of IFN-gamma+ CD8 T cells are displayed in each plot. C Frequency of MUC-1-, hTERT-, NY-ESO-1-, CEA- and pooled TAA-specific CD8 T cell responses in patients (grey) and healthy controls (black). Fisher exact test, * p=0.0179; ns=not significant.ConclusionsThe presence of circulating T cells responding to CEA in all 5 patients, but also to MUC-1 and hTERT in 3 patients suggests that these TAAs may be good targets for immunotherapy in CRC. Our findings also provide a rationale to investigate the prognostic value of CEA-, MUC-1- and hTERT-specific T cells in the peripheral blood of CRC patients and to consider vaccination with these antigens to boost or induce responses to control residual tumor post-surgery.Ethics ApprovalThis study was approved by Health Sciences North’s Research Ethics Board; approval number 18- 104.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals Protection against Vaccinia Virus Challenge by CD8 Memory T Cells Resolved by Molecular Mimicry

2006 ◽  
Vol 81 (2) ◽  
pp. 934-944 ◽  
Author(s):  
Markus Cornberg ◽  
Brian S. Sheridan ◽  
Frances M. Saccoccio ◽  
Michael A. Brehm ◽  
Liisa K. Selin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vaccinia Virus ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Molecular Mimicry ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Epitopes ◽  
Cell Responses

ABSTRACT Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and a subdominant epitope, VV-a11r198, did generate cross-reactive responses to LCMV. Infection with VV induced strong epitope-specific responses which were stable into long-term memory and peaked at the time virus was cleared, consistent with CD8 T cells assisting in the control of VV. Two different approaches, direct adoptive transfer of VV-e7r-specific CD8 T cells and prior immunization with a VV-e7r-expressing ubiquitinated minigene, demonstrated that memory CD8 T cells alone could play a significant role in protective immunity against VV. These studies suggest that exploiting cross-reactive responses between viruses may be a useful tool to complement existing technology in predicting immunogenic epitopes to large viruses, such as VV, leading to a better understanding of the role CD8 T cells play during these viral infections.

scholarly journals Adrenergic signaling controls early transcriptional programs during CD8+ T cell responses to viral infection

2021 ◽  
Author(s):  
Leonardo Estrada ◽  
Didem Agac Cobanoglu ◽  
Aaron Wise ◽  
Robert Maples ◽  
Murat Can Cobanoglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Receptor Activation ◽  
Cell Development ◽  
Primary Response ◽  
Cell Responses

Viral infections drive the expansion and differentiation of responding CD8+ T cells into variegated populations of cytolytic effector and memory cells. While pro-inflammatory cytokines and cell surface immune receptors play a key role in guiding T cell responses to infection, T cells are also markedly influenced by neurotransmitters. Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the beta2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Ralpha; in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

scholarly journals Modulation of let-7 miRNAs controls the differentiation of effector CD8 T cells

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Alexandria C Wells ◽  
Keith A Daniels ◽  
Constance C Angelou ◽  
Eric Fagerberg ◽  
Amy S Burnside ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Activated T Cells ◽  
Cell Responses

The differentiation of naive CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful antiviral, and antitumor immune responses. Here, using a mouse model, we describe a dual role for the let-7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naive phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor-mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7-mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses.

scholarly journals Single cell profiling of T and B cell repertoires following SARS-CoV-2 mRNA vaccine

2021 ◽  
Author(s):  
Suhas Sureshchandra ◽  
Sloan A. Lewis ◽  
Brianna Doratt ◽  
Allen Jankeel ◽  
Izabela Ibraim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Natural Infection ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Responses

mRNA based vaccines for SARS-CoV-2 have shown exceptional clinical efficacy providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used single-cell RNA sequencing and functional assays to compare humoral and cellular responses to two doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4 T cells, and robust antigen-specific polyfunctional CD4 T cell responses in all vaccinees. On the other hand, CD8 T cell responses were both weak and variable. Interestingly, clonally expanded CD8 T cells were observed in every vaccinee, as observed following natural infection. TCR gene usage, however, was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of larger CD8 T cell clones occupied distinct clusters, likely due to the recognition of a broader set of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response where early CD4 T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8 T cells, together capable of contributing to future recall responses.

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