scholarly journals Airway delivery of both a BCG prime and adenoviral boost drives CD4 and CD8 T cells into the lung tissue parenchyma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daryan A. Kaveh ◽  
M. Carmen Garcia-Pelayo ◽  
Naomi C. Bull ◽  
Pedro J. Sanchez-Cordon ◽  
John Spiropoulos ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Tissue ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Vaccine Development ◽  
Lung Parenchyma ◽  
Boost Vaccination ◽  
Parenteral Delivery ◽  
Promising Strategy ◽  
Intravascular Staining

Abstract Heterologous BCG prime-boost regimens represent a promising strategy for an urgently required improved tuberculosis vaccine. Identifying the mechanisms which underpin the enhanced protection induced by such strategies is one key aim which would significantly accelerate rational vaccine development. Experimentally, airway vaccination induces greater efficacy than parenteral delivery; in both conventional vaccination and heterologous boosting of parenteral BCG immunisation. However, the effect of delivering both the component prime and boost immunisations via the airway is not well known. Here we investigate delivery of both the BCG prime and adenovirus boost vaccination via the airway in a murine model, and demonstrate this approach may be able to improve the protective outcome over parenteral prime/airway boost. Intravascular staining of T cells in the lung revealed that the airway prime regimen induced more antigen-specific multifunctional CD4 and CD8 T cells to the lung parenchyma prior to challenge and indicated the route of both prime and boost to be critical to the location of induced resident T cells in the lung. Further, in the absence of a defined phenotype of vaccine-induced protection to tuberculosis; the magnitude and phenotype of vaccine-specific T cells in the parenchyma of the lung may provide insights into potential correlates of immunity.

Defective lung CD8+ T cells lacking NFATc2 induced lung metastasis in NFATc2 deficient mice in a bronchoalveolar adenocarcinoma murine model

Pneumologie ◽  
2007 ◽  
Vol 61 (01) ◽  
Author(s):  
JH Maxeiner ◽  
R Karwot ◽  
K Sauer ◽  
P Scholtes ◽  
R Wiewrodt ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Metastasis ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Deficient Mice

scholarly journals Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer

2021 ◽  
Vol 118 (23) ◽  
pp. e2100588118
Author(s):  
Pengcheng Wei ◽  
Kimberly R. Jordan ◽  
Jonathan D. Buhrman ◽  
Jun Lei ◽  
Hexiang Deng ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Amino Acid Substitution ◽  
Cd8 T Cells ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Single Amino Acid ◽  
Cell Repertoire ◽  
Subtle Change

Tumors frequently express unmutated self-tumor–associated antigens (self-TAAs). However, trial results using self-TAAs as vaccine targets against cancer are mixed, often attributed to deletion of T cells with high-affinity receptors (TCRs) for self-TAAs during T cell development. Mutating these weak self-TAAs to produce higher affinity, effective vaccines is challenging, since the mutations may not benefit all members of the broad self-TAA–specific T cell repertoire. We previously identified a common weak murine self-TAA that we converted to a highly effective antitumor vaccine by a single amino acid substitution. In this case the modified and natural self-TAAs still raised very similar sets of CD8 T cells. Our structural studies herein show that the modification of the self-TAA resulted in a subtle change in the major histocompatibility complex I–TAA structure. This amino acid substitution allowed a dramatic conformational change in the peptide during subsequent TCR engagement, creating a large increase in TCR affinity and accounting for the efficacy of the modified self-TAA as a vaccine. These results show that carefully selected, well-characterized modifications to a poorly immunogenic self-TAA can rescue the immune response of the large repertoire of weakly responding natural self-TAA–specific CD8 T cells, driving them to proliferate and differentiate into functional effectors. Subsequently, the unmodified self-TAA on the tumor cells, while unable to drive this response, is nevertheless a sufficient target for the CD8 cytotoxic effectors. Our results suggest a pathway for more efficiently identifying variants of common self-TAAs, which could be useful in vaccine development, complementing other current nonantigen-specific immunotherapies.

scholarly journals 754 TIGIT-PVR is a key immune checkpoint and therapeutic target in HPV-positive head and neck squamous cell carcinomas

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A788-A788
Author(s):  
Xiuning Le ◽  
Minghao Dang ◽  
Venkatesh Hegde ◽  
Bo Jiang ◽  
Ravaen Slay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Immune Checkpoint ◽  
Therapeutic Target ◽  
Therapeutic Efficacy ◽  
Cd8 T Cell ◽  
Immune Checkpoints ◽  
Rna Seq

BackgroundHuman papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HPV+ HNSCC) is a disease that has moderate response to anti-PD-1/L1 immune checkpoint blockade, with the response rates less than 20% and median progression-free survival less than 3 months. A greater understanding of tumor intrinsic and extrinsic factors that restrict anti-tumor immunity in the tumor immune microenvironment (TIME) is needed to identify other immune checkpoints to enhance therapeutic efficacy.MethodsTwo cohorts (TCGA n=72 and a separate cohort n=84) of surgically resected, treatment-naïve HPV+ HNSCC with RNA-seq were analyzed to understand the immune features. In addition, single-cell RNA-seq and TCR-seq were performed on 18 cases to further delineate the immune molecules' interactions. An immune-competent murine HPV+ HNSCC model was used to preliminarily evaluate the therapeutic efficacy.ResultsIn two bulk-sequenced HPV+ HNSCC cohorts, TIGIT ligands PVR and NECTIN2 were found to associate with an epithelial-to-mesenchymal gene expression signature, suppression of IFNα and IFNγ signaling, a stromal-enriched or immune-excluded TIME, and poor survival. Single-cell RNA-seq of over 72,000 cells of HPV+ HNSCC revealed that the PVR/NECTIN ligand TIGIT was highly prevalent in T-cells (34%), significantly higher than PD1- (20%, p<0.01). There is an enrichment of cell-cell interactions mediated by TIGIT-PVR/NECTIN2 in the TIME of HPV+HNSCC versus normal tonsil. TIGIT was the most differentially upregulated immune checkpoint on clonally expanded CD8+T-cells and was abundant on antigen-experienced, tissue-resident memory CD8+T-cell and T-regulatory subsets. TIGIT ligands PVR, NECTIN1, and NECTIN2 were abundant on mature regulatory dendritic cells (DCs), immunosuppressive plasmacytoid (p)DCs, and macrophages, respectively. TIGIT and PD-1 co-blockade in the mEER syngeneic murine model significantly reduced tumor growth, improved survival, restored effector function of HPV16E7-specific CD8+T cells, natural killer cells, and DCs, and conferred tumor re-challenge protection.ConclusionsTIGIT-PVR/NECTIN receptors/ligands are more abundant than PD-1/L1 in the TIME of HPV+ HNSCC. Co-blockade of TIGIT and PD-1 immune checkpoints enhanced anti-tumor efficacy in a CD8+ T-cell-dependent manner and conferred long-term immune protection in a murine model. Our study nominates TIGIT as a therapeutic target for HPV+ HNSCC.

Enumeration of human antigen–specific naive CD8+ T cells reveals conserved precursor frequencies

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3718-3725 ◽  
Author(s):  
Cécile Alanio ◽  
Fabrice Lemaitre ◽  
Helen K. W. Law ◽  
Milena Hasan ◽  
Matthew L. Albert
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Vaccine Development ◽  
Direct Detection ◽  
Magnetic Bead ◽  
Cell Precursor ◽  
Adaptive Immune ◽  
Precursor Frequency ◽  
Magnetic Bead Enrichment ◽  
Hiv 1

Abstract The number of antigen-specific naive CD8+ T cells is believed to be important in the shaping of adaptive immune responses, and is predictive for the magnitude of priming responses in mouse models. Because of extremely low precursor frequencies, knowledge about these cells comes from indirect techniques and estimations. Here, we present a strategy based on the combination of tetramer staining, magnetic-bead enrichment, and multiparametric cytometry, which permitted direct detection and analysis of CD8+ T cells reactive for 6 different naive epitopes (MART-126-35, HIV-1 Gag p1777-85, hepatitis C virus [HCV] NS31406-1415, HCV Core132-140, NY-ESO-1157-165, and cytomegalovirus [CMV] pp65495-503). Interestingly, we detected higher than 100-fold differences in precursor frequency across these epitopes (from 0.6 × 10−6 to 1.3 × 10−4), but conserved frequencies among humans. Development of a procedure for direct assessment of T-cell precursor frequency in humans has important implications, with particular relevance to vaccine development and monitoring of tumor and self-reactive T cells.

scholarly journals Resident memory CD8 T cells persist for years in human small intestine

2019 ◽  
Vol 216 (10) ◽  
pp. 2412-2426 ◽  
Author(s):  
Raquel Bartolomé-Casado ◽  
Ole J.B. Landsverk ◽  
Sudhir Kumar Chauhan ◽  
Lisa Richter ◽  
Danh Phung ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
Lamina Propria ◽  
Cd8 T Cells ◽  
Vaccine Development ◽  
Oral Vaccines ◽  
Memory Cd8 T Cells ◽  
Immune Mediated ◽  
Tnf Α ◽  
Bona Fide

Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for &gt;1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.

Interleukin 12 in Combination with Tumor Cell Vaccines Elicits Anti-Leukemic Immune Responses in a Murine Model of Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4482-4482
Author(s):  
Tanja A. Gruber ◽  
Dianne C. Skelton ◽  
Donald B. Kohn
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Lymphoblastic Leukemia ◽  
Lethal Dose ◽  
Philadelphia Chromosome ◽  
Leukemia Cells ◽  
Immunologic Memory

Abstract Current intensive chemotherapy regimens have dramatically increased survival in acute lymphoblastic leukemia (ALL) patients compared to the 1950s when single agent chemotherapy was used. Despite this success certain subsets of patients have a high rate of relapse such as those with the Philadelphia chromosome (Ph+). Because the Bcr-Abl oncogene is a novel protein product and uniquely expressed in the leukemia clone, it has the potential to generate anti-leukemic immune responses. Our lab has been studying immunotheraputic approaches for Ph+ ALL using a murine model. Previous data have demonstrated that transduction of leukemia cells with the immunomodulators CD40Ligand, CD80, and GM-CSF generate T and NK cell immune responses. When irradiated and given as a vaccine these gene-modified cells are able to protect a portion of mice from an otherwise lethal dose of leukemia. We looked at the ability to systemic IL-12 treatments to potentiate this immune response and found that IL-12 alone was able to eliminate pre-existing disease in mice. IL-12 treatments, however, did not establish immunologic memory and did not protect mice from subsequent re-challenge with a lethal dose of leukemia. IL-12 protection was primarily mediated by CD4 and CD8 T cells as demonstrated by a decrease in survival in nude mice. When CD4 or CD8 T cells were depleted individually, however, protection was maintained indicating that one cell type can compensate for the other in its absence. Depletion of NK cells from Nude mice further decreased survival indicating a role for these cells in the protection. Thus protection was mediated in part by CD4 T lymphocytes, CD8 T lymphocytes, and Natural Killer cells. The ability of IL-12 to activate three different cell types may explain the efficacy seen in this model, where other cytokines alone have failed. In combination, IL-12 and our leukemia cell vaccine are effective in eliminating pre-established aggressive Philadelphia chromosome positive leukemia and establishing long lasting immunity from subsequent lethal doses of wild type leukemia. As expected, the immunologic memory generated by vaccination with gene modified leukemia cells was mediated by CD4 T cells as indicated by depletion studies. These studies demonstrate the feasibility of immunotheraputic approaches in the treatment of Ph+ ALL.

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