scholarly journals Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Mauro Di Pilato ◽  
Miguel Palomino-Segura ◽  
Ernesto Mejías-Pérez ◽  
Carmen E. Gómez ◽  
Andrea Rubio-Ponce ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Adaptive Immune System ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

scholarly journals Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

2011 ◽  
Vol 19 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Jin Huk Choi ◽  
Joe Dekker ◽  
Stephen C. Schafer ◽  
Jobby John ◽  
Craig E. Whitfill ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Transduction Efficiency ◽  
Virus Antibody ◽  
Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

scholarly journals Negligible impact of SARS-CoV-2 variants on CD4+ and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees.

2021 ◽  
Author(s):  
Alison Tarke ◽  
John Sidney ◽  
Nils Methot ◽  
Yun Zhang ◽  
Jennifer M Dan ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Comprehensive Analysis ◽  
T Cell Epitopes ◽  
Cell Reactivity ◽  
Cell Responses ◽  
Adaptive Immune ◽  
T Cell Reactivity

The emergence of SARS-CoV-2 variants highlighted the need to better understand adaptive immune responses to this virus. It is important to address whether also CD4+ and CD8+ T cell responses are affected, because of the role they play in disease resolution and modulation of COVID-19 disease severity. Here we performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. Similarly, we demonstrate that the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.

scholarly journals The GM-CSF–IRF5 signaling axis in eosinophils promotes antitumor immunity through activation of type 1 T cell responses

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Isabelle C. Arnold ◽  
Mariela Artola-Boran ◽  
Alessandra Gurtner ◽  
Katrin Bertram ◽  
Michael Bauer ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Immunity ◽  
Critical Role ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Tumor Control ◽  
Gm Csf ◽  
Cell Responses

The depletion of eosinophils represents an efficient strategy to alleviate allergic asthma, but the consequences of prolonged eosinophil deficiency for human health remain poorly understood. We show here that the ablation of eosinophils severely compromises antitumor immunity in syngeneic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+ T cell responses. The specific loss of GM-CSF signaling or IRF5 expression in the eosinophil compartment phenocopies the loss of the entire lineage. GM-CSF activates IRF5 in vitro and in vivo and can be administered recombinantly to improve tumor immunity. IL-10 counterregulates IRF5 activation by GM-CSF. CRC patients whose tumors are infiltrated by large numbers of eosinophils also exhibit robust CD8 T cell infiltrates and have a better prognosis than patients with eosinophillow tumors. The combined results demonstrate a critical role of eosinophils in tumor control in CRC and introduce the GM-CSF–IRF5 axis as a critical driver of the antitumor activities of this versatile cell type.

Dasatinib inhibits recombinant viral antigen-specific murine CD4+ and CD8+ T-cell responses and NK-cell cytolytic activity in vitro and in vivo

2009 ◽  
Vol 37 (2) ◽  
pp. 256-265 ◽  
Author(s):  
Cara K. Fraser ◽  
Stephen J. Blake ◽  
Kerrilyn R. Diener ◽  
A. Bruce Lyons ◽  
Michael P. Brown ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Antigen ◽  
Nk Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cytolytic Activity ◽  
Cell Responses

scholarly journals Malaria Blood Stage Suppression of Liver Stage Immunity by Dendritic Cells

2003 ◽  
Vol 197 (2) ◽  
pp. 143-151 ◽  
Author(s):  
Carlos Ocaña-Morgner ◽  
Maria M. Mota ◽  
Ana Rodriguez
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Blood Stage ◽  
Liver Stage ◽  
Cell Responses ◽  
Blood Stage Infection ◽  
Stage Infection

Malaria starts with Plasmodium sporozoites infection of the host's liver, where development into blood stage parasites occurs. It is not clear why natural infections do not induce protection against the initial liver stage and generate low CD8+ T cell responses. Using a rodent malaria model, we show that Plasmodium blood stage infection suppresses CD8+ T cell immune responses that were induced against the initial liver stage. Blood stage Plasmodium affects dendritic cell (DC) functions, inhibiting maturation and the capacity to initiate immune responses and inverting the interleukin (IL)-12/IL-10 secretion pattern. The interaction of blood stage parasites with DCs induces the secretion of soluble factors that inhibit the activation of CD8+ T cells in vitro and the suppression of protective CD8+ T cell responses against the liver stage in vivo. We propose that blood stage infection induces DCs to suppress CD8+ T cell responses in natural malaria infections. This evasion mechanism leaves the host unprotected against reinfection by inhibiting the immune response against the initial liver stage of the disease.

scholarly journals Increasing the potency of dendritic cell based vaccines for the treatment of cancer

2021 ◽  
Author(s):  
◽  
Dianne Sika-Paotonu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Vaccination Strategies ◽  
Monophosphoryl Lipid A ◽  
Tlr Agonist

<p>Tumours can be eradicated by T cells that recognise unique tumour-associated antigens. These T cells are initially stimulated by dendritic cells (DCs) that have acquired antigens from tumour tissue. Vaccination strategies that increase the frequencies of tumour-specific T cells by enhancing the activity of DCs are being evaluated in the clinic as novel cancer therapies. Our hypothesis is that existing DC-based vaccination strategies can be improved by stimulating toll-like receptor (TLR) signalling in the DCs, and also by encouraging interactions with iNKT cells, as these two activities are known to enhance DC function. It was also hypothesised that superior T cell responses could be induced by combining these two activities together. We used the TLR 4 agonist monophosphoryl lipid A (MPL) alone and in combination with other TLR agonists to achieve effective activation of bone marrow-derived DCs (BM-DCs) cultured in-vitro, which was characterised by upregulated expression of maturation markers on the cell surface, and enhanced release of pro-inflammatory cytokines. Some TLR agonist combinations provided significantly enhanced activities in this regard, notably the combination of MPL with either the TLR 2 agonist Pam3Cys, or the TLR 7/8 agonist Resiquimod. Although in-vitro activated BM-DCs were unable to induce stronger antigen-specific CD8+ T cell responses after intravenous injection when compared to BMDCs without TLR stimulation, enhanced CD8+ T cell responses were achieved in-vivo with the co-administration of TLR ligands, implying that TLR stimulation needed to act on cells of the host. Further studies identified the langerin-expressing CD8ɑ+ splenic DC subset in the spleen as recipients of antigen that was transferred from injected cells, and that these recipients were participants in the cross-presentation and T cell priming activities driving the CD8+ T cell response after vaccination. Antigen-loaded BM-DCs carrying the NKT cell ligand ɑ-galactosylceramide (ɑ-GalCer) were found to consistently increase antigen-specific CD8+ T cell responses in-vivo, and also cytotoxic responses as seen in cytotoxic killing assays. Again, langerin-expressing CD8ɑ+ splenic DCs were shown to be involved in this response by acquiring antigen and ɑ-GalCer from the injected vaccine BM-DCs. Finally, it was possible to achieve even greater CD8+ T cell responses in-vivo by injecting BM-DCs carrying antigen and ɑ-GalCer, together with timely co-administration of the TLR agonist. These results suggest a reassessment of the activities of DC-based vaccines to include the important role of “courier” to DCs already resident in the host that can be exploited to improve vaccination outcomes.</p>

scholarly journals Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3713-3722 ◽  
Author(s):  
Juliette Mouriès ◽  
Gabriel Moron ◽  
Géraldine Schlecht ◽  
Nicolas Escriou ◽  
Gilles Dadaglio ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Antigen Processing ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses

Abstract Cross-presentation is a crucial mechanism in tumoral and microbial immunity because it allows internalized cell associated or exogenous antigens (Ags) to be delivered into the major histocompatibility complex I pathway. This pathway is important for the development of CD8+ T-cell responses and for the induction of tolerance. In mice, cross-presentation is considered to be a unique property of CD8α+ conventional dendritic cells (DCs). Here we show that splenic plasmacytoid DCs (pDCs) efficiently capture exogenous Ags in vivo but are not able to cross-present these Ags at steady state. However, in vitro and in vivo stimulation by Toll-like receptor-7, or -9 or viruses licenses pDCs to cross-present soluble or particulate Ags by a transporter associated with antigen processing-dependent mechanism. Induction of cross-presentation confers to pDCs the ability to generate efficient effector CD8+ T-cell responses against exogenous Ags in vivo, showing that pDCs may play a crucial role in induction of adaptive immune responses against pathogens that do not infect tissues of hemopoietic origin. This study provides the first evidence for an in vivo role of splenic pDCs in Ag cross-presentation and T-cell cross-priming and suggests that pDCs may constitute an attractive target to boost the efficacy of vaccines based on cytotoxic T lymphocyte induction.

scholarly journals Systems Immunology Analyses Following Porcine Respiratory and Reproductive Syndrome Virus Infection and Vaccination

2021 ◽  
Vol 12 ◽  
Author(s):  
Loïc Vivien Bocard ◽  
Andrew Robert Kick ◽  
Corinne Hug ◽  
Heidi Erika Lisa Lischer ◽  
Tobias Käser ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Innate Immune ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Cell Responses ◽  
Adaptive Immune

This study was initiated to better understand the nature of innate immune responses and the relatively weak and delayed immune response against porcine reproductive and respiratory syndrome virus (PRRSV). Following modified live virus (MLV) vaccination or infection with two PRRSV-2 strains, we analyzed the transcriptome of peripheral blood mononuclear cells collected before and at three and seven days after vaccination or infection. We used blood transcriptional modules (BTMs)-based gene set enrichment analyses. BTMs related to innate immune processes were upregulated by PRRSV-2 strains but downregulated by MLV. In contrast, BTMs related to adaptive immune responses, in particular T cells and cell cycle, were downregulated by PRRSV-2 but upregulated by MLV. In addition, we found differences between the PRRSV strains. Only the more virulent strain induced a strong platelet activation, dendritic cell activation, interferon type I and plasma cell responses. We also calculated the correlations of BTM with the neutralizing antibody and the T-cell responses. Early downregulation (day 0–3) of dendritic cell and B-cell BTM correlated to both CD4 and CD8 T-cell responses. Furthermore, a late (day 3–7) upregulation of interferon type I modules strongly correlated to helper and regulatory T-cell responses, while inflammatory BTM upregulation correlated more to CD8 T-cell responses. BTM related to T cells had positive correlations at three days but negative associations at seven days post-infection. Taken together, this work contributes to resolve the complexity of the innate and adaptive immune responses against PRRSV and indicates a fundamentally different immune response to the less immunogenic MLV compared to field strains which induced robust adaptive immune responses. The identified correlates of T-cell responses will facilitate a rational approach to improve the immunogenicity of MLV.

scholarly journals Increasing the potency of dendritic cell based vaccines for the treatment of cancer

2021 ◽  
Author(s):  
◽  
Dianne Sika-Paotonu
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Vaccination Strategies ◽  
Monophosphoryl Lipid A ◽  
Tlr Agonist

<p>Tumours can be eradicated by T cells that recognise unique tumour-associated antigens. These T cells are initially stimulated by dendritic cells (DCs) that have acquired antigens from tumour tissue. Vaccination strategies that increase the frequencies of tumour-specific T cells by enhancing the activity of DCs are being evaluated in the clinic as novel cancer therapies. Our hypothesis is that existing DC-based vaccination strategies can be improved by stimulating toll-like receptor (TLR) signalling in the DCs, and also by encouraging interactions with iNKT cells, as these two activities are known to enhance DC function. It was also hypothesised that superior T cell responses could be induced by combining these two activities together. We used the TLR 4 agonist monophosphoryl lipid A (MPL) alone and in combination with other TLR agonists to achieve effective activation of bone marrow-derived DCs (BM-DCs) cultured in-vitro, which was characterised by upregulated expression of maturation markers on the cell surface, and enhanced release of pro-inflammatory cytokines. Some TLR agonist combinations provided significantly enhanced activities in this regard, notably the combination of MPL with either the TLR 2 agonist Pam3Cys, or the TLR 7/8 agonist Resiquimod. Although in-vitro activated BM-DCs were unable to induce stronger antigen-specific CD8+ T cell responses after intravenous injection when compared to BMDCs without TLR stimulation, enhanced CD8+ T cell responses were achieved in-vivo with the co-administration of TLR ligands, implying that TLR stimulation needed to act on cells of the host. Further studies identified the langerin-expressing CD8ɑ+ splenic DC subset in the spleen as recipients of antigen that was transferred from injected cells, and that these recipients were participants in the cross-presentation and T cell priming activities driving the CD8+ T cell response after vaccination. Antigen-loaded BM-DCs carrying the NKT cell ligand ɑ-galactosylceramide (ɑ-GalCer) were found to consistently increase antigen-specific CD8+ T cell responses in-vivo, and also cytotoxic responses as seen in cytotoxic killing assays. Again, langerin-expressing CD8ɑ+ splenic DCs were shown to be involved in this response by acquiring antigen and ɑ-GalCer from the injected vaccine BM-DCs. Finally, it was possible to achieve even greater CD8+ T cell responses in-vivo by injecting BM-DCs carrying antigen and ɑ-GalCer, together with timely co-administration of the TLR agonist. These results suggest a reassessment of the activities of DC-based vaccines to include the important role of “courier” to DCs already resident in the host that can be exploited to improve vaccination outcomes.</p>

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.

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