Faculty Opinions recommendation of Cross-presentation of human cytomegalovirus pp65 (UL83) to CD8+ T cells is regulated by virus-induced, soluble-mediator-dependent maturation of dendritic cells.

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.

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Outer membrane vesicles engineered to express membrane-bound antigen program dendritic cells for cross-presentation to CD8+ T cells

Acta Biomaterialia ◽

10.1016/j.actbio.2019.04.033 ◽

2019 ◽

Vol 91 ◽

pp. 248-257 ◽

Cited By ~ 12

Author(s):

Sjoerd T.T. Schetters ◽

Wouter S.P. Jong ◽

Sophie K. Horrevorts ◽

Laura J.W. Kruijssen ◽

Steef Engels ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Outer Membrane ◽

Cd8 T Cells ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Cross Presentation ◽

Membrane Bound

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IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Blood ◽

10.1182/blood-2011-06-363564 ◽

2012 ◽

Vol 119 (6) ◽

pp. 1407-1417 ◽

Cited By ~ 87

Author(s):

Francesca Spadaro ◽

Caterina Lapenta ◽

Simona Donati ◽

Laura Abalsamo ◽

Vincenzo Barnaba ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class I ◽

Cd8 T Cells ◽

Tumor Development ◽

Class I ◽

Cross Presentation ◽

The Cross ◽

Human Dendritic Cells

Abstract Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8+ T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8+ T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing–dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.

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Constitutive versus Activation-dependent Cross-Presentation of Immune Complexes by CD8+ and CD8− Dendritic Cells In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.20020295 ◽

2002 ◽

Vol 196 (6) ◽

pp. 817-827 ◽

Cited By ~ 230

Author(s):

Joke M.M. den Haan ◽

Michael J. Bevan

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Mhc Class I ◽

Cd8 T Cells ◽

Immune Complexes ◽

Class I ◽

Cross Presentation ◽

Deficient Mice ◽

Mhc Class I Molecules

Murine splenic dendritic cells (DCs) can be divided into two subsets based on CD8α expression, but the specific role of each subset in stimulation of T cells is largely unknown. An important function of DCs is the ability to take up exogenous antigens and cross-present them in the context of major histocompatibility complex (MHC) class I molecules to CD8+ T cells. We previously demonstrated that, when cell-associated ovalbumin (OVA) is injected into mice, only the CD8+ DC subset cross-presents OVA in the context of MHC class I. In contrast to this selectivity with cell-associated antigen, we show here that both DC subsets isolated from mice injected with OVA/anti-OVA immune complexes (OVA-IC) cross-present OVA to CD8+ T cells. The use of immunoglobulin G Fc receptor (FcγR) common γ-chain–deficient mice revealed that the cross-presentation by CD8− DCs depended on the expression of γ-chain–containing activating FcγRs, whereas cross-presentation by CD8+ DCs was not reduced in γ-chain–deficient mice. These results suggest that although CD8+ DCs constitutively cross-present exogenous antigens in the context of MHC class I molecules, CD8− DCs only do so after activation, such as via ligation of FcγRs. Cross-presentation of immune complexes may play an important role in autoimmune diseases and the therapeutic effect of antitumor antibodies.

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Host ER–parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii–infected dendritic cells

Journal of Experimental Medicine ◽

10.1084/jem.20082108 ◽

2009 ◽

Vol 206 (2) ◽

pp. 399-410 ◽

Cited By ~ 115

Author(s):

Romina S. Goldszmid ◽

Isabelle Coppens ◽

Avital Lev ◽

Pat Caspar ◽

Ira Mellman ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Toxoplasma Gondii ◽

Mhc Class I ◽

Cd8 T Cells ◽

Parasitophorous Vacuole ◽

Host Cells ◽

Class I ◽

Cross Presentation ◽

Infected Cells

Toxoplasma gondii tachyzoites infect host cells by an active invasion process leading to the formation of a specialized compartment, the parasitophorous vacuole (PV). PVs resist fusion with host cell endosomes and lysosomes and are thus distinct from phagosomes. Because the parasite remains sequestered within the PV, it is unclear how T. gondii–derived antigens (Ag’s) access the major histocompatibility complex (MHC) class I pathway for presentation to CD8+ T cells. We demonstrate that recruitment of host endoplasmic reticulum (hER) to the PV in T. gondii–infected dendritic cells (DCs) directly correlates with cross-priming of CD8+ T cells. Furthermore, we document by immunoelectron microscopy the transfer of hER components into the PV, a process indicative of direct fusion between the two compartments. In strong contrast, no association between hER and phagosomes or Ag presentation activity was observed in DCs containing phagocytosed live or dead parasites. Importantly, cross-presentation of parasite-derived Ag in actively infected cells was blocked when hER retrotranslocation was inhibited, indicating that the hER serves as a conduit for the transport of Ag between the PV and host cytosol. Collectively, these findings demonstrate that pathogen-driven hER–PV interaction can serve as an important mechanism for Ag entry into the MHC class I pathway and CD8+ T cell cross-priming.

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Dendritic cells that phagocytose apoptotic macrophages loaded with mycobacterial antigens activate CD8 T cells via cross-presentation

PLoS ONE ◽

10.1371/journal.pone.0182126 ◽

2017 ◽

Vol 12 (8) ◽

pp. e0182126 ◽

Cited By ~ 11

Author(s):

Patricia Espinosa-Cueto ◽

Alejandro Magallanes-Puebla ◽

Carlos Castellanos ◽

Raul Mancilla

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Cross Presentation ◽

Mycobacterial Antigens

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Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1520627112 ◽

2015 ◽

Vol 112 (47) ◽

pp. 14664-14669 ◽

Cited By ~ 22

Author(s):

Anand K. Katakam ◽

Hans Brightbill ◽

Christian Franci ◽

Chung Kung ◽

Victor Nunez ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Lymphoid Organs ◽

Serine Threonine Kinase ◽

Cross Presentation ◽

Inflammatory Stimuli ◽

Dc Maturation

Dendritic cells (DCs) link innate and adaptive immunity and use a host of innate immune and inflammatory receptors to respond to pathogens and inflammatory stimuli. Although DC maturation via canonical NF-κB signaling is critical for many of these functions, the role of noncanonical NF-κB signaling via the serine/threonine kinase NIK (NF-κB–inducing kinase) remains unclear. Because NIK-deficient mice lack secondary lymphoid organs, we generated transgenic mice with targeted NIK deletion in CD11c+ cells. Although these mice exhibited normal lymphoid organs, they were defective in cross-priming naive CD8+ T cells following vaccination, even in the presence of anti-CD40 or polyinosinic:polycytidylic acid to induce DC maturation. This impairment reflected two intrinsic defects observed in splenic CD8+ DCs in vitro, namely antigen cross-presentation to CD8+ T cells and secretion of IL-12p40, a cytokine known to promote cross-priming in vivo. In contrast, antigen presentation to CD4+ T cells was not affected. These findings reveal that NIK, and thus probably the noncanonical NF-κB pathway, is critical to allow DCs to acquire the capacity to cross-present antigen and prime CD8 T cells after exposure to licensing stimuli, such as an agonistic anti-CD40 antibody or Toll-like receptor 3 ligand.

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