scholarly journals Expansion of effector and memory T cells is associated with increased survival in recurrent glioblastomas treated with dendritic cell immunotherapy

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Marica Eoli ◽  
Cristina Corbetta ◽  
Elena Anghileri ◽  
Natalia Di Ianni ◽  
Micaela Milani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Memory T Cells ◽  
Therapeutic Modality ◽  
Effector Memory ◽  
Autologous Tumor ◽  
Vaccine Site

Abstract Background The efficacy of dendritic cell (DC) immunotherapy as a single therapeutic modality for the treatment of glioblastoma (GBM) patients remains limited. In this study, we evaluated in patients with GBM recurrence the immune-mediated effects of DC loaded with autologous tumor lysate combined with temozolomide (TMZ) or tetanus toxoid (TT). Methods In the phase I-II clinical study DENDR2, 12 patients were treated with 5 DC vaccinations combined with dose-dense TMZ. Subsequently, in eight patients, here defined as Variant (V)-DENDR2, the vaccine site was preconditioned with TT 24 hours before DC vaccination and TMZ was avoided. As a survival endpoint for these studies, we considered overall survival 9 months (OS9) after second surgery. Patients were analyzed for the generation of effector, memory, and T helper immune response. Results Four of 12 DENDR2 patients reached OS9, but all failed to show an immunological response. Five of eight V-DENDR2 patients (62%) reached OS9, and one patient is still alive (OS >30 months). A robust CD8+ T-cell activation and memory T-cell formation were observed in V-DENDR2 OS>9. Only in these patients, the vaccine-specific CD4+ T-cell activation (CD38+/HLA-DR+) was paralleled by an increase in TT-induced CD4+/CD38low/CD127high memory T cells. Only V-DENDR2 patients showed the formation of a nodule at the DC injection site infiltrated by CCL3-expressing CD4+ T cells. Conclusions TT preconditioning of the vaccine site and lack of TMZ could contribute to the efficacy of DC immunotherapy by inducing an effector response, memory, and helper T-cell generation.

scholarly journals Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation

2021 ◽  
Author(s):  
Blagoje Soskic ◽  
Eddie Cano-Gamez ◽  
Deborah J. Smyth ◽  
Kirsty Ambridge ◽  
Ziying Ke ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Memory T Cells ◽  
Disease Risk ◽  
Effector Memory ◽  
Immune Disease ◽  
Time Points

AbstractDuring activation, T cells undergo extensive changes in gene expression which shape the properties of cells to exert their effector function. Therefore, understanding the genetic regulation of gene expression during T cell activation provides essential insights into how genetic variants influence the response to infections and immune diseases. We generated a single-cell map of expression quantitative trait loci (eQTL) across a T cell activation time-course. We profiled 655,349 CD4+ naive and memory T cells, capturing transcriptional states of unstimulated cells and three time points of cell activation in 119 healthy individuals. We identified 38 cell clusters, including stable clusters such as central and effector memory T cells and transient clusters that were only present at individual time points of activation, such as interferon-responding cells. We mapped eQTLs using a T cell activation trajectory and identified 6,407 eQTL genes, of which a third (2,265 genes) were dynamically regulated during T cell activation. We integrated this information with GWAS variants for immune-mediated diseases and observed 127 colocalizations, with significant enrichment in dynamic eQTLs. Immune disease loci colocalized with genes that are involved in the regulation of T cell activation, and genes with similar functions tended to be perturbed in the same direction by disease risk alleles. Our results emphasize the importance of mapping context-specific gene expression regulation, provide insights into the mechanisms of genetic susceptibility of immune diseases, and help prioritize new therapeutic targets.

scholarly journals Interferon regulatory factor 4 controls effector functions of CD8+ memory T cells

2021 ◽  
Vol 118 (16) ◽  
pp. e2014553118
Author(s):  
Aenne Harberts ◽  
Constantin Schmidt ◽  
Joanna Schmid ◽  
Daniel Reimers ◽  
Friedrich Koch-Nolte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
T Cell Activation ◽  
Cell Activation ◽  
Memory T Cells ◽  
Memory Cell ◽  
Effector Memory ◽  
Effector Cells ◽  
Effector Functions

The transcription factor IRF4 is required for CD8+ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8+ T cell responses. The function of IRF4 in memory CD8+ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8+ memory T cells, we used a mouse model with tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8+ memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8+ memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8+ effector memory T cells, CD8+ tissue-resident memory T cells (TRM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8+ TRM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8+ memory T cells. Formation and maintenance of CD8+ TRM cells, in contrast, appear to depend on IRF4.

Parasite species regulates T cell activation in human malaria

2021 ◽  
Author(s):  
Florian Bach ◽  
Diana Munoz Sandoval ◽  
Michalina Mazurczyk ◽  
Yrene Themistocleous ◽  
Thomas A Rawlinson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plasmodium Vivax ◽  
T Cell Activation ◽  
Cell Activation ◽  
Parasite Species ◽  
Field Isolate ◽  
Effector Memory ◽  
Lymphoid Tissues ◽  
Systems Immunology

Plasmodium vivax offers unique challenges for malaria control and may prove a more difficult species to eradicate than Plasmodium falciparum. Yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. In this study, we inoculated human volunteers with a clonal field isolate of P. vivax and used systems immunology tools to track their response through infection and convalescence. Our data reveal Plasmodium vivax triggers an acute phase response that shares remarkable overlap with that of P. falciparum, suggesting a hardwired innate response that does not differentiate between parasite species. This leads to the global recruitment of innate-like and adaptive T cells into lymphoid tissues where up to one quarter of the T cell compartment is activated. Heterogeneous effector memory-like CD4+ T cells dominate this response and their activation coincides with collateral tissue damage. Remarkably, comparative transcriptional analyses show that P. falciparum drives even higher levels of T cell activation; diverging T cell responses may therefore explain why falciparum malaria more frequently causes severe disease.

scholarly journals Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19

2020 ◽  
Author(s):  
Anno Saris ◽  
Tom D.Y. Reijnders ◽  
Esther J. Nossent ◽  
Alex R. Schuurman ◽  
Jan Verhoeff ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Effector Memory ◽  
Activated T Cells ◽  
Immune Profile ◽  
Prolonged Icu Stay

AbstractOur understanding of the coronavirus disease-19 (COVID-19) immune response is almost exclusively derived from studies that examined blood. To gain insight in the pulmonary immune response we analysed BALF samples and paired blood samples from 17 severe COVID-19 patients. Macrophages and T cells were the most abundant cells in BALF. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells and expressed higher levels of the exhaustion marker PD-1 than in peripheral blood. Prolonged ICU stay associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. In conclusion, the bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood.SummaryThe bronchoalveolar immune response in severe COVID-19 strongly differs from the peripheral blood immune profile. Fatal COVID-19 associated with T cell activation blood, but not in BALF.

EP.WE.805From bench to bedside; A rationale for Immunotherapy in the adjuvant setting for Oesophageal cancer

2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Noel Donlon ◽  
Maria Davern ◽  
Andrew Sheppard ◽  
John Reynolds ◽  
Joanne Lysaght
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Single Agent ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Post Surgery ◽  
Post Operative Period

Abstract Background Immunotherapy is being intensively investigated for its utilisation in the curative setting as a single agent and in the multimodal setting, however, the most appropriate time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumour immunity perioperatively to provide a rationale for adjuvant immunotherapy. Methods Systemic immunity was immunophenotyped pre and post-oesophagectomy on days 0, 1, 3, 7 and week 6 by flow cytometry (n = 14). The frequency of circulating lymphocytes, T cells, cytotoxic and helper T lymphocytes was profiled longitudinally including the proportion of T cell subsets in circulation. This study also profiled immune checkpoint expression on circulating T cells including: PD-1, CTLA-4, TIGIT, TIM-3, LAG-3, PD-L1 and PD-L2. Markers of immunogenicity (calreticulin, HMGB1 and MIC-A/B) were also assessed. Results The frequency of circulating CD27 + T cells increases sequentially in the immediate post-operative period peaking on day 7 in OAC patients. (p < 0.01) There is a sequential decrease in the percentage of effector memory and central memory T cells in circulation and an increase in the percentage of naïve T cells in peripheral circulation of OAC patients in the immediate post-operative period. The expression of CTLA-4 on the surface of circulating CD4 + T cells decreases 6 weeks post-operatively in OAC patients. Conclusions We observed increased T cell activation and immune checkpoints immediately post-surgery with returns to baseline by week 6. These results suggest that immune checkpoint inhibitors such as anti-PD-1 may be beneficial immediately post-surgery to maintain T cell activation and prevent exhaustion of this increased population of activated T cells observed immediately post-surgery.

TREM-1 modulates dendritic cell maturation and dendritic cell–mediated T cell activation induced by ox-LDL

2020 ◽  
Author(s):  
Yunkai Wang ◽  
Jie Wang ◽  
Lu Han ◽  
Yun Li Shen ◽  
Jie Yun You ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Human Peripheral Blood ◽  
Dendritic Cell Maturation ◽  
Cell Maturation ◽  
Blood Monocytes

Abstract Background: Triggering receptor expressed on myeloid cells (TREM)-1is identified as a major upstream proatherogenic receptor. However, the cellular processes modulated by TREM-1 in the development of atherosclerosis and plaque destabilization has not been fully elucidated. In this study, we investigated the effects of TREM-1 on dendritic cell maturation and dendritic cell–mediated T-cell activation induced by oxidized low-density lipoprotein (ox-LDL) in atherogenesis. Methods: Human peripheral blood monocytes were differentiated to dendritic cells and stimulated by ox-LDL. Naive autologous T cells were co-cultured with pretreated dendritic cells.The expressionof TREM-1 and the production of inflammatory cytokines were assessed by real-time PCR, western blot and ELISA.The expression of immune factors was determined with FACS to evaluate dendritic cell maturation and T-cell activation. Results: Stimulation with ox-LDL promoted dendritic cell maturation, TREM-1 expression and T-cell activation, and exposure of T cells to ox-LDL-treated dendritic cells induced production of interferon-γ and IL-17. Blocking TREM-1 suppressed dendritic cell maturation with low expression of CD1a, CD40, CD86 and HLA-DR, decreased production of TNF-α, IL-1β, IL-6 and MCP-1, and increased secretion of TGF-β and IL-10. In addition, stimulation of ox-LDL induced miR-155, miR-27, Let-7c and miR-185 expression, whereas inhibition of TREM-1 repressed miRNA-155. Silencing TREM-1 or miRNA-155 increased SOCS1 expression induced by ox-LDL. T cells derived from carotid atherosclerotic plaques or healthy individuals showed similar result patterns. Conclusion: These data suggest that TREM-1 modulates maturation of dendritic cells and activation of plaque T cells induced by ox-LDL, a pivotal player in atherogenesis.

Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor–reactive cytotoxic T lymphocytes

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2436-2442 ◽  
Author(s):  
Ettore Biagi ◽  
Gianpietro Dotti ◽  
Eric Yvon ◽  
Edward Lee ◽  
Martin Pule ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antibody Therapy ◽  
Interferon Γ ◽  
Lymphocytic Leukemia ◽  
Cytotoxic T Cell ◽  
Autologous Tumor ◽  
Molecular Transfer

AbstractClinical benefits from monoclonal antibody therapy for B-chronic lymphocytic leukemia (B-CLL) have increased interest in developing additional immunotherapies for the disease. CD40 ligand is an accessory signal for T-cell activation and can overcome T-cell anergy. The OX40-OX40 ligand pathway is involved in the subsequent expansion of memory antigen-specific T cells. We expressed both CD40L and OX40L on B-CLL cells by exploiting the phenomenon of molecular transfer from fibroblasts overexpressing these ligands. We analyzed the effects of the modified B-CLL cells on the number, phenotype, and cytotoxic function of autologous T cells in 7 B-CLL patients. Transfer of CD40L and OX40L was observed in all and was followed by the up-regulation of B7-1 and B7-2. The culture of CD40L/OX40L-expressing B-CLL cells with autologous T cells generated CD4+/CD8+ cytotoxic T-cell lines, which secreted interferon-γ (IFN-γ) and granzyme-B/perforin in response to autologous, but not to allogeneic, B-CLL cells or to autologous T-cell blasts. CD40L or OX40L alone was insufficient to expand tumor-reactive T cells. The combination of CD40L and OX40L on B-CLL cells may allow the generation of therapeutic immune responses to B-CLL, either by active immunization with modified tumor cells or by adoptive immunotherapy with tumor-reactive autologous T cells.

scholarly journals CD8+ T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver

Cell Reports ◽  
2018 ◽  
Vol 25 (1) ◽  
pp. 68-79.e4 ◽  
Author(s):  
Lauren E. Holz ◽  
Julia E. Prier ◽  
David Freestone ◽  
Thiago M. Steiner ◽  
Kieran English ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Liver Tissue ◽  
Cell Activation ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Resident Memory T Cells

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

DOCK8-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 658-658
Author(s):  
Stephanie C. Eisenbarth ◽  
Jeanne E. Hendrickson ◽  
Samuele Calabro ◽  
Antonia Gallman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Innate Immune ◽  
Allogeneic Response ◽  
Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. The relative role of dendritic cells, B cells and macrophages in the induction of RBC alloimmunization remain unclear. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused RBCs. A particularly useful transgenic "HOD mouse" has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffyb blood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune cells or receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the GEF (guanine nucleotide exchange factor) DOCK8 fail to develop alloimmunity to transfused RBCs. Dendritic cells in these knockout mice fail to migrate to T cells due to lack of coordinated actin rearrangement governed by this GEF. Both B cell and T cell activation in the spleen to the transgenic transfused RBCs is abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in DOCK8-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. Our preliminary data now suggest that DOCK8-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The need for dendritic cell migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed; these mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion and the specific role of splenic dendritic cell subsets in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

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