Peptide-Loaded Langerhans Cells, Despite Increased IL15 Secretion and T-Cell Activation In Vitro, Elicit Antitumor T-Cell Responses Comparable to Peptide-Loaded Monocyte-Derived Dendritic Cells In Vivo

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.

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

Blood ◽

10.1182/blood-2008-12-192252 ◽

2009 ◽

Vol 113 (23) ◽

pp. 5793-5800 ◽

Cited By ~ 27

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20100619 ◽

2011 ◽

Vol 208 (3) ◽

pp. 577-592 ◽

Cited By ~ 262

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.

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

10.21203/rs.3.rs-636850/v1 ◽

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.

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Dendritic cells overexpressing CD95 (Fas) ligand elicit vigorous allospecific T-cell responses in vivo

Blood ◽

10.1182/blood-2002-07-2042 ◽

2003 ◽

Vol 101 (4) ◽

pp. 1469-1476 ◽

Cited By ~ 35

Author(s):

Sofia Buonocore ◽

Frédéric Paulart ◽

Alain Le Moine ◽

Michel Braun ◽

Isabelle Salmon ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Fas Ligand ◽

T Cell Responses ◽

Genetically Engineered ◽

Peripheral Tolerance ◽

Cytotoxic T Cell ◽

Cell Responses

Dendritic cells (DCs) genetically engineered to overexpress CD95 (Fas) ligand (CD95L-DC) were proposed as tools to induce peripheral tolerance to alloantigens. Herein, we observed that CD95L-DC obtained after retroviral gene transfer in bone marrow (BM) precursors derived from CD95-deficient (lpr/lpr) mice elicit much stronger allospecific type 1 helper T-cell and cytotoxic T-cell activities than control DCs upon injection in vivo, although they induce lower T-cell responses in vitro. Indeed, a single injection of CD95L-DC prepared from C57BL/6 mice was sufficient to prime bm13 recipients for acute rejection of C57BL/6 skin allografts that were otherwise tolerated in the context of this single weak major histocompatibility complex (MHC) class I incompatibility. Massive neutrophil infiltrates depending on interleukin (IL)–1 signaling were observed at sites of CD95L-DC injection. Experiments in IL-1 receptor–deficient mice or in animals injected with depleting anti-Gr1 monoclonal antibody (mAb) established that neutrophil recruitment is required for the development of vigorous T-cell responses after injection of CD95L-DC in vivo.

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Indirect inhibition of in vivo and in vitro T-cell responses by intravenous immunoglobulins due to impaired antigen presentation

Blood ◽

10.1182/blood-2009-06-225417 ◽

2010 ◽

Vol 115 (9) ◽

pp. 1727-1734 ◽

Cited By ~ 61

Author(s):

Éric Aubin ◽

Réal Lemieux ◽

Renée Bazin

Keyword(s):

T Cell ◽

Antigen Presentation ◽

T Cell Activation ◽

T Cell Responses ◽

Antigen Presenting Cells ◽

In Vivo Model ◽

Cell Responses ◽

Antigen Presenting

Abstract Several clinical studies done with intravenous immunoglobulin (IVIg)–treated autoimmune patients as well as several in vitro studies have revealed that IVIg can reduce polyclonal T-cell activation and modify their cytokine secretion pattern. However, their effect on (auto)antigen-specific T-cell responses has never been addressed directly. In the present work, we used an in vivo model of induction of antigen-specific T-cell responses and an in vitro antigen presentation system to study the effects of IVIg on T-cell responses. The results obtained showed that IVIg inhibited both the in vivo and in vitro antigen-specific T-cell responses but that this effect was the indirect consequence of a reduction in the antigen presentation ability of antigen-presenting cells. The inhibitory effect of IVIg was FcγRIIb-independent, suggesting that IVIg must interfere with activating FcγRs expressed on antigen-presenting cells to reduce their ability to present antigens. Such inhibition of T-cell responses by reducing antigen presentation may therefore contribute to the well-known anti-inflammatory effects of IVIg in autoimmune diseases.

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Dendritic Cell Responses to Early Murine Cytomegalovirus Infection

Journal of Experimental Medicine ◽

10.1084/jem.20021522 ◽

2003 ◽

Vol 197 (7) ◽

pp. 885-898 ◽

Cited By ~ 272

Author(s):

Marc Dalod ◽

Tanya Hamilton ◽

Rachelle Salomon ◽

Thais P. Salazar-Mather ◽

Stanley C. Henry ◽

...

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Lymphocyte Activation ◽

Murine Cytomegalovirus ◽

Cell Responses ◽

Dc Maturation

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.

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Visualising the interaction of CD4 T cells and DCs in the evolution of inflammatory arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-212279 ◽

2018 ◽

Vol 77 (4) ◽

pp. 579-588 ◽

Cited By ~ 10

Author(s):

Catriona T Prendergast ◽

Agapitos Patakas ◽

Shaima Al-Khabouri ◽

Claire L McIntyre ◽

Iain B McInnes ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

T Cell Responses ◽

Receptor Expression ◽

Phenotypic Analysis ◽

Necrosis Factor Alpha ◽

Cell Responses

ObjectivesSuccessful early intervention in rheumatoid arthritis (RA) with the aim of resetting immunological tolerance requires a clearer understanding of how specificity, cellular kinetics and spatial behaviour shape the evolution of articular T cell responses. We aimed to define initial seeding of articular CD4+ T cell responses in early experimental arthritis, evaluating their dynamic behaviour and interactions with dendritic cells (DCs) in the inflamed articular environment.MethodsAntigen-induced arthritis was used to model articular inflammation. Flow cytometry and PCR of T cell receptor (TCR) diversity genes allowed phenotypic analysis of infiltrating T cells. The dynamic interactions of T cells with joint residing DCs were visualised using intravital multiphoton microscopy.ResultsInitial recruitment of antigen-specific T cells into the joint was paralleled by accumulation of CD4+ T cells with diverse antigen-receptor expression and ability to produce tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) on mitogenic restimulation. A proportion of this infiltrate demonstrated slower motility speeds and engaged for longer periods with articular DCs in vivo. Abatacept treatment did not disrupt these interactions but did reduce T cell expression of inducible costimulatory (ICOS) molecule. We also demonstrated that non-specific CD4+ T cells could be recruited during these early articular events.ConclusionsWe demonstrate that CD4+ T cells engage with articular DCs supporting antigen specific T cell reactivation. This cellular dialogue can be targeted therapeutically to reduce local T cell activation.

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Differentiation of myeloid dendritic cells into CD8α-positive dendritic cells in vivo

Blood ◽

10.1182/blood.v96.5.1865.h8001865_1865_1872 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1865-1872 ◽

Cited By ~ 2

Author(s):

Miriam Merad ◽

Lawrence Fong ◽

Jakob Bogenberger ◽

Edgar G. Engleman

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Wild Type Mouse ◽

Interleukin 12 ◽

Myeloid Dendritic Cells ◽

Myeloid Antigens

Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) with varying phenotypes. For example, in mice, CD8α+ and CD8α− DC are thought to represent cells of lymphoid and myeloid origin, respectively. Langerhans cells (LC) of the epidermis are typical myeloid DC; they do not express CD8α, but they do express high levels of myeloid antigens such as CD11b and FcγR. By contrast, thymic DC, which derive from a lymphoid-related progenitor, express CD8α but only low levels of myeloid antigens. CD8α+ DC are also found in the spleen and lymph nodes (LN), but the origin of these cells has not been determined. By activating and labeling CD8α− epidermal LC in vivo, it was found that these cells expressed CD8α on migration to the draining LN. Similarly, CD8α− LC generated in vitro from a CD8 wild-type mouse and injected into the skin of a CD8αKO mouse expressed CD8α when they reached the draining LN. The results also show that CD8α+ LC are potent APC. After migration from skin, they localized in the T-cell areas of LN, secreted high levels of interleukin-12, interferon-γ, and chemokine-attracting T cells, and they induced antigen-specific T-cell activation. These results demonstrate that myeloid DC in the periphery can express CD8α when they migrate to the draining LN. CD8α expression on these DC appears to reflect a state of activation, mobilization, or both, rather than lineage.

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