scholarly journals MAIT cell activation augments adenovirus vector vaccine immunogenicity

Science ◽  
2021 ◽  
Vol 371 (6528) ◽  
pp. 521-526 ◽  
Author(s):  
Nicholas M. Provine ◽  
Ali Amini ◽  
Lucy C. Garner ◽  
Alexandra J. Spencer ◽  
Christina Dold ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Plasmacytoid Dendritic Cell ◽  
T Cell Responses ◽  
Adjuvant Activity ◽  
Mait Cells ◽  
Cell Responses ◽  
Adenovirus Vectors ◽  
Mait Cell

Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)–derived interferon (IFN)–α and monocyte-derived interleukin-18. IFN-α–induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell–deficient mice displayed impaired CD8+ T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.

scholarly journals Virus-based vaccine vectors with distinct replication mechanisms differentially infect and activate dendritic cells

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Carolina Chiale ◽  
Anthony M. Marchese ◽  
Yoichi Furuya ◽  
Michael D. Robek
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Virus Replication ◽  
T Cell Activation ◽  
Viral Vectors ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cell Responses ◽  
Identical Cell

AbstractThe precise mechanism by which many virus-based vectors activate immune responses remains unknown. Dendritic cells (DCs) play key roles in priming T cell responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not always well understood. We hypothesized that highly immunogenic viral vectors with identical cell entry pathways but unique replication mechanisms differentially infect and activate DCs to promote antigen presentation and activation of distinctive antigen-specific T cell responses. To evaluate differences in replication mechanisms, we utilized a rhabdovirus vector (vesicular stomatitis virus; VSV) and an alphavirus-rhabdovirus hybrid vector (virus-like vesicles; VLV), which replicates like an alphavirus but enters the cell via the VSV glycoprotein. We found that while virus replication promotes CD8+ T cell activation by VLV, replication is absolutely required for VSV-induced responses. DC subtypes were differentially infected in vitro with VSV and VLV, and displayed differences in activation following infection that were dependent on vector replication but were independent of interferon receptor signaling. Additionally, the ability of the alphavirus-based vector to generate functional CD8+ T cells in the absence of replication relied on cDC1 cells. These results highlight the differential activation of DCs following infection with unique viral vectors and indicate potentially discrete roles of DC subtypes in activating the immune response following immunization with vectors that have distinct replication mechanisms.

scholarly journals Sustained IFN-I stimulation impairs MAIT cell responses to bacteria by inducing IL-10 during chronic HIV-1 infection

2020 ◽  
Vol 6 (8) ◽  
pp. eaaz0374 ◽  
Author(s):  
X. Tang ◽  
S. Zhang ◽  
Q. Peng ◽  
L. Ling ◽  
H. Shi ◽  
...  
Keyword(s):  
Cell Activation ◽  
Surface Protein ◽  
Interleukin 10 ◽  
Mait Cells ◽  
Cell Dysfunction ◽  
Cell Responses ◽  
High Level ◽  
Hiv 1 ◽  
Mait Cell

Mucosal-associated invariant T (MAIT) cells in HIV-1–infected individuals are functionally impaired by poorly understood mechanisms. Single-cell transcriptional and surface protein analyses revealed that peripheral MAIT cells from HIV-1–infected subjects were highly activated with the up-regulation of interferon (IFN)–stimulated genes as compared to healthy individuals. Sustained IFN-α treatment suppressed MAIT cell responses to Escherichia coli by triggering high-level interleukin-10 (IL-10) production by monocytes, which subsequently inhibited the secretion of IL-12, a crucial costimulatory cytokine for MAIT cell activation. Blocking IFN-α or IL-10 receptors prevented MAIT cell dysfunction induced by HIV-1 exposure in vitro. Moreover, blocking the IL-10 receptor significantly improved anti–Mycobacterium tuberculosis responses of MAIT cells from HIV-1–infected patients. Our findings demonstrate the central role of the IFN-I/IL-10 axis in MAIT cell dysfunction during HIV-1 infection, which has implications for the development of anti–IFN-I/IL-10 strategies against bacterial coinfections in HIV-1–infected patients.

scholarly journals Selection and T-cell antigenicity of synthetic long peptides derived from SARS-CoV-2

2022 ◽  
Vol 103 (1) ◽  
Author(s):  
Katarzyna Piadel ◽  
Amin Haybatollahi ◽  
Angus George Dalgleish ◽  
Peter Lawrence Smith
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
Hla Class I ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses

The pandemic caused by SARS-CoV-2 has led to the successful development of effective vaccines however the prospect of variants of SARS-CoV-2 and future coronavirus outbreaks necessitates the investigation of other vaccine strategies capable of broadening vaccine mediated T-cell responses and potentially providing cross-immunity. In this study the SARS-CoV-2 proteome was assessed for clusters of immunogenic epitopes restricted to diverse human leucocyte antigen. These regions were then assessed for their conservation amongst other coronaviruses representative of different alpha and beta coronavirus genera. Sixteen highly conserved peptides containing numerous HLA class I and II restricted epitopes were synthesized from these regions and assessed in vitro for their antigenicity against T-cells from individuals with previous SARS-CoV-2 infection. Monocyte derived dendritic cells were generated from these peripheral blood mononuclear cells (PBMC), loaded with SARS-CoV-2 peptides, and used to induce autologous CD4+ and CD8+ T cell activation. The SARS-CoV-2 peptides demonstrated antigenicity against the T-cells from individuals with previous SARS-CoV-2 infection indicating that this approach holds promise as a method to activate anti-SAR-CoV-2 T-cell responses from conserved regions of the virus which are not included in vaccines utilising the Spike protein.

scholarly journals Regulation of T cell-dendritic cell interactions by IL-7 governs T-cell activation and homeostasis

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5793-5800 ◽  
Author(s):  
Manoj Saini ◽  
Claire Pearson ◽  
Benedict Seddon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Tcr Signaling ◽  
Cell Responses

Abstract Interleukin-7 (IL-7) plays a central role in the homeostasis of the T-cell compartment by regulating T-cell survival and proliferation. Whether IL-7 can influence T-cell receptor (TCR) signaling in T cells remains controversial. Here, using IL-7–deficient hosts and TCR-transgenic T cells that conditionally express IL-7R, we examined antigen-specific T-cell responses in vitro and in vivo to viral infection and lymphopenia to determine whether IL-7 signaling influences TCR-triggered cell division events. In vitro, we could find no evidence that IL-7 signaling could costimulate T-cell activation over a broad range of conditions, suggesting that IL-7 does not directly tune TCR signaling. In vivo, however, we found an acute requirement for IL-7 signaling for efficiently triggering T-cell responses to influenza A virus challenge. Furthermore, we found that IL-7 was required for the enhanced homeostatic TCR signaling that drives lymphopenia-induced proliferation by a mechanism involving efficient contacts of T cells with dendritic cells. Consistent with this, saturating antigen-presenting capacity in vivo overcame the triggering defect in response to cognate peptide. Thus, we demonstrate a novel role for IL-7 in regulating T cell–dendritic cell interactions that is essential for both T-cell homeostasis and activation in vivo.

scholarly journals VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses

2011 ◽  
Vol 208 (3) ◽  
pp. 577-592 ◽  
Author(s):  
Li Wang ◽  
Rotem Rubinstein ◽  
Janet L. Lines ◽  
Anna Wasiuk ◽  
Cory Ahonen ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Surveillance ◽  
T Cell Responses ◽  
Cell Responses ◽  
Ig Superfamily ◽  
B7 Family

The immunoglobulin (Ig) superfamily consists of many critical immune regulators, including the B7 family ligands and receptors. In this study, we identify a novel and structurally distinct Ig superfamily inhibitory ligand, whose extracellular domain bears homology to the B7 family ligand PD-L1. This molecule is designated V-domain Ig suppressor of T cell activation (VISTA). VISTA is primarily expressed on hematopoietic cells, and VISTA expression is highly regulated on myeloid antigen-presenting cells (APCs) and T cells. A soluble VISTA-Ig fusion protein or VISTA expression on APCs inhibits T cell proliferation and cytokine production in vitro. A VISTA-specific monoclonal antibody interferes with VISTA-induced suppression of T cell responses by VISTA-expressing APCs in vitro. Furthermore, anti-VISTA treatment exacerbates the development of the T cell–mediated autoimmune disease experimental autoimmune encephalomyelitis in mice. Finally, VISTA overexpression on tumor cells interferes with protective antitumor immunity in vivo in mice. These findings show that VISTA, a novel immunoregulatory molecule, has functional activities that are nonredundant with other Ig superfamily members and may play a role in the development of autoimmunity and immune surveillance in cancer.

scholarly journals Structure-activity mapping of the peptide- and force-dependent landscape of T-cell activation

2021 ◽  
Author(s):  
Yinnian Feng ◽  
Xiang Zhao ◽  
Adam K. White ◽  
K. Christopher Garcia ◽  
Polly M. Fordyce
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
T Cell Responses ◽  
Antigenic Peptides ◽  
Mhc Molecules ◽  
Cell Responses ◽  
Biomechanical Force ◽  
Biomechanical Forces

SUMMARYAdaptive immunity relies on T lymphocytes that use αβ T-cell receptors (TCRs) to discriminate amongst peptides presented by MHC molecules (pMHCs). An enhanced ability to screen for pMHCs capable of inducing robust T-cell responses could have broad applications in diagnosing and treating immune diseases. T cell activation relies on biomechanical forces to initiate triggering of the TCR. Yet, most in vitro screening technologies for antigenic peptides test potential pMHCs for T cell binding without force and thus are often not predictive of activating peptides. Here, we present a technology that uses biomechanical force to initiate T cell triggering in high throughput. BATTLES (Biomechanically-Assisted T-cell Triggering for Large-scale Exogenous-pMHC Screening) displays candidate pMHCs on spectrally encoded ‘smart beads’ capable of applying physiological loads to T cells, facilitating exploration of the force- and sequence-dependent landscape of T-cell responses. BATTLES can be used to explore basic T-cell mechanobiology and T cell-based immunotherapies.

scholarly journals Efficient targeting of NY-ESO-1 tumor antigen to human cDC1s by lymphotactin results in cross-presentation and antigen-specific T cell expansion

2021 ◽  
Author(s):  
Camille M Le Gall ◽  
Anna Cammarata ◽  
Lukas de Haas ◽  
Ivan Ramos-Tomillero ◽  
Jorge Cuenca-Escalona ◽  
...  
Keyword(s):  
New York ◽  
T Cell ◽  
T Cell Activation ◽  
Tumor Antigen ◽  
Cell Activation ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Antigen Delivery ◽  
Cell Responses

Type 1 conventional dendritic cells (cDC1s) are characterized by their ability to induce potent CD8+ T cell responses. In efforts to generate novel vaccination strategies, notably against cancer, human cDC1s emerge as an ideal target to deliver antigens. cDC1s uniquely express XCR1, a seven transmembrane G protein-coupled receptor (GPCR). Due to its restricted expression and endocytic nature, XCR1 represents an attractive receptor to mediate antigen-delivery to human cDC1s. To explore tumor antigen delivery to human cDC1s, we used an engineered version of XCR1-binding lymphotactin (XCL1), XCL1(CC3). Site-specific sortase-mediated transpeptidation was performed to conjugate XCL1(CC3) to an analog of the HLA-A*02:01 epitope of the cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1). While poor epitope solubility prevented isolation of stable XCL1-antigen conjugates, incorporation of a single polyethylene glycol (PEG) chain upstream of the epitope-containing peptide enabled generation of soluble XCL1(CC3)-antigen fusion constructs. Binding and chemotactic characteristics of the XCL1-antigen conjugate, as well as its ability to induce antigen-specific CD8+ T cell activation by cDC1s, was assessed. PEGylated XCL1(CC3)-antigen conjugates retained binding to XCR1, and induced cDC1 chemoattraction in vitro. The model epitope was efficiently cross-presented by human cDC1s to activate NY-ESO-1-specific CD8+ T cells. Importantly, vaccine activity was increased by targeting XCR1 at the surface of cDC1s. Our results present a novel strategy for the generation of targeted vaccines fused to insoluble antigens. Moreover, our data emphasize the potential of targeting XCR1 at the surface of primary human cDC1s to induce potent CD8+ T cell responses.

scholarly journals Structure-activity mapping of the peptide- and force-dependent landscape of T-cell activation

2021 ◽  
Author(s):  
Polly Fordyce ◽  
Yinnian Feng ◽  
Xiang Zhao ◽  
Adam White ◽  
K. Garcia
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Large Scale ◽  
Cell Activation ◽  
T Cell Responses ◽  
Screening Tests ◽  
Mhc Molecules ◽  
Cell Responses

Abstract Adaptive immunity relies on T lymphocytes that use αβ T-cell receptors (TCRs) to discriminate amongst peptides presented by MHC molecules (pMHCs). An enhanced ability to screen for pMHCs capable of inducing robust T-cell responses could have broad applications in diagnosing and treating immune diseases. T-cell activation in vivo relies on biomechanical forces to trigger activation by sparse antigenic pMHCs. However, in vitro screening tests potential pMHCs without force and at high (non-physiological) pMHC densities and thus often fails to predict potent agonists in vivo. Here, we present a technology that uses biomechanical force to initiate T-cell triggering in high throughput. BATTLES (Biomechanically-Assisted T-cell Triggering for Large-scale Exogenous-pMHC Screening) displays candidate pMHCs on spectrally encoded ‘smart beads’ capable of applying physiological loads to T cells, facilitating exploration of the force- and sequence-dependent landscape of T-cell responses. BATTLES can be used to explore basic T-cell mechanobiology and T cell-based immunotherapies.

Sign in / Sign up

Export Citation Format

Share Document