Dietary salt and endothelin A receptor activation regulates T cell responses in a tissue‐dependent manner

The unprecedented and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19-vaccinated nonhuman primates seroconverted rapidly and exhibited a detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they had reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides a durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2.

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

10.1101/2021.10.20.465178 ◽

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.

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A nanoparticle vaccine that targets neoantigen peptides to lymphoid tissues elicits robust antitumor T cell responses

npj Vaccines ◽

10.1038/s41541-020-00253-9 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Carlos A. Arbelaez ◽

Juan Estrada ◽

Melissa A. Gessner ◽

Charles Glaus ◽

Agnieszka B. Morales ◽

...

Keyword(s):

T Cell ◽

Tumor Growth ◽

Tumor Antigens ◽

T Cell Responses ◽

Tumor Growth Inhibition ◽

Lymphoid Tissues ◽

Dependent Manner ◽

Kras Mutations ◽

Peptide Antigens ◽

Cell Responses

AbstractCancer vaccines using synthetic long peptides (SLP) targeting tumor antigens have been tested in the clinic but the outcomes have been unimpressive, perhaps because these peptides elicit predominantly CD4+ T cell responses. We hypothesized that enhanced delivery of peptide antigens to, and uptake in, secondary lymphoid tissues should elicit more robust CD8+ and CD4+ T cell responses and improved anti-tumor responses. Here, we have designed SLP-containing cationic lipoplexes (SLP–Lpx) that improve delivery of peptides to myeloid cells in the spleen and lymphatics. Using the G12D KRAS mutations as neoantigens, we found that vaccination of mice with naked synthetic peptides harboring the G12D mutation with CpG adjuvant stimulated mainly CD4+ T cell responses with limited tumor growth inhibition. On the other hand, immunization with SLP–Lpx stimulated both CD4+ and CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner. Combination of the SLP–Lpx vaccines with a checkpoint inhibitor led to profound growth suppression of established tumors. These studies suggest that preferential targeting of peptides derived from neoantigens to the spleen via lipoplexes elicits potent CD4+ and CD8+ T cell responses that inhibit tumor growth.

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Belatacept Can Inhibit Allo-Specific T Cell Responses in a Donor-Dependent Manner But Preserves Virus-Specific Memory T Cell-Responses.

Transplantation Journal ◽

10.1097/00007890-201407151-00115 ◽

2014 ◽

Vol 98 ◽

pp. 36

Author(s):

C. Falk ◽

K. Daemen ◽

M. Stevanovic-Meyer ◽

F. Lehner ◽

H. Haller ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Dependent Manner ◽

Memory T Cell ◽

Cell Responses ◽

Specific Memory

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Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion

Journal of Experimental Medicine ◽

10.1084/jem.20121172 ◽

2012 ◽

Vol 210 (1) ◽

pp. 99-114 ◽

Cited By ~ 194

Author(s):

Dimitra Peppa ◽

Upkar S. Gill ◽

Gary Reynolds ◽

Nicholas J.W. Easom ◽

Laura J. Pallett ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hepatitis B ◽

Nk Cells ◽

Human Liver ◽

Large Population ◽

Death Receptor ◽

T Cell Responses ◽

Dependent Manner ◽

Cell Responses

Antiviral T cell responses in hepatotropic viral infections such as hepatitis B virus (HBV) are profoundly diminished and prone to apoptotic deletion. In this study, we investigate whether the large population of activated NK cells in the human liver contributes to this process. We show that in vitro removal of NK cells augments circulating CD8+ T cell responses directed against HBV, but not against well-controlled viruses, in patients with chronic hepatitis B (CHB). We find that NK cells can rapidly eliminate HBV-specific T cells in a contact-dependent manner. CD8+ T cells in the liver microcirculation are visualized making intimate contact with NK cells, which are the main intrahepatic lymphocytes expressing TNF-related apoptosis-inducing ligand (TRAIL) in CHB. High-level expression of the TRAIL death receptor TRAIL-R2 is found to be a hallmark of T cells exposed to the milieu of the HBV-infected liver in patients with active disease. Up-regulation of TRAIL-R2 renders T cells susceptible to caspase-8–mediated apoptosis, from which they can be partially rescued by blockade of this death receptor pathway. Our findings demonstrate that NK cells can negatively regulate antiviral immunity in chronic HBV infection and illustrate a novel mechanism of T cell tolerance in the human liver.

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Specific immunotherapy modifies allergen-specific CD4+ T-cell responses in an epitope-dependent manner

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2013.10.054 ◽

2014 ◽

Vol 133 (3) ◽

pp. 872-879.e7 ◽

Cited By ~ 75

Author(s):

Erik Wambre ◽

Jonathan H. DeLong ◽

Eddie A. James ◽

Nadia Torres-Chinn ◽

Wolfgang Pfützner ◽

...

Keyword(s):

T Cell ◽

Specific Immunotherapy ◽

T Cell Responses ◽

Cd4 T Cell ◽

Dependent Manner ◽

Cell Responses

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Differential Regulation of Antigen-Specific CD8+ T Cell Responses by IL-12p40 in a Dose-Dependent Manner

The Journal of Immunology ◽

10.4049/jimmunol.180.11.7167 ◽

2008 ◽

Vol 180 (11) ◽

pp. 7167-7174 ◽

Cited By ~ 9

Author(s):

Doo-Jin Kim ◽

Je-In Youn ◽

Sang-Hwan Seo ◽

Hyun-Tak Jin ◽

Young-Chul Sung

Keyword(s):

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Differential Regulation ◽

Dependent Manner ◽

Cell Responses ◽

Dose Dependent

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CpG and Interleukin-15 Synergize to Enhance IFN-γ Production by Activated CD8+T Cells

BioMed Research International ◽

10.1155/2013/924023 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Dustin Cobb ◽

Siqi Guo ◽

Ronald B. Smeltz

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Responses ◽

Dependent Manner ◽

Infectious Agents ◽

Cell Responses ◽

Striking Increase ◽

Physiological Relevance ◽

Interleukin 15 ◽

Ifn Γ

Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8+T cells. Paradoxically, we previously reported that IL-15 could enhance CD8+T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8+T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN-γby CD8+T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN-γproduction. The effect of CpG and IL-15 was also evident with CD8+T cells recovered from mice infected with the parasiteTrypanosoma cruzi(T. cruzi) and restimulated with antigen. The observed synergy between CpG and IL-15 occurred in an IL-12-dependent manner, and this effect could even be demonstrated in cocultures of activated CD8+T cells and CD4+CD25+regulatory T cells. Although IFN-γwas not essential for CpG-induced IL-12, the ability of CpG and IL-15 to act on CD8+T cells required expression of the IFN-γ-inducible transcription factor T-bet. These data have important implications for development of vaccines and design of therapies to boost CD8+T-cell responses to infectious agents and tumors.

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Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

10.1101/535385 ◽

2019 ◽

Cited By ~ 3

Author(s):

Nicola Trendel ◽

Philipp Kruger ◽

Stephanie Gaglione ◽

John Nguyen ◽

Johannes Pettmann ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cytokine Production ◽

Mechanistic Model ◽

T Cell Responses ◽

Dependent Manner ◽

Antigen Stimulation ◽

Cell Responses ◽

Perfect Adaptation ◽

Wide Range

AbstractMaintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A pre-diction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings high-light that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses.

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