scholarly journals Cytomegalovirus Misleads Its Host by Priming of CD8 T Cells Specific for an Epitope Not Presented in Infected Tissues

2003 ◽  
Vol 199 (1) ◽  
pp. 131-136 ◽  
Author(s):  
Rafaela Holtappels ◽  
Jürgen Podlech ◽  
Marcus-Folker Pahl-Seibert ◽  
Markus Jülch ◽  
Doris Thomas ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Evasion ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Antigenic Peptide ◽  
Long Term Memory ◽  
Antigenic Peptides ◽  
Cross Presentation ◽  
Antigen Presenting

Cytomegaloviruses (CMVs) code for several proteins that inhibit the presentation of antigenic peptides to CD8 T cells. Although the molecular mechanisms of CMV interference with the major histocompatibility complex class I pathway are long understood, surprisingly little evidence exists to support a role in vivo. Here we document the first example of the presentation of an antigenic peptide being blocked by a CMV immune evasion protein in organs relevant to CMV disease. Although this Db-restricted peptide, which is derived from the antiapoptotic protein M45 of murine CMV (mCMV), is classified as an immunodominant peptide based on response magnitude and long-term memory, adoptive transfer of M45 epitope-specific CD8 T cells did not protect against infection with wild-type mCMV. Notably, the same cells protected C57BL/6 mice infected with an mCMV mutant in which immune evasion protein m152/gp40 is deleted. These data indicate that direct presentation or cross-presentation of an antigenic peptide by professional antigen-presenting cells can efficiently prime CD8 T cells that fail in protection against CMV organ disease because m152/gp40 prevents presentation of this peptide in pathogenetically relevant tissue cells.

scholarly journals Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

2004 ◽  
Vol 200 (3) ◽  
pp. 297-306 ◽  
Author(s):  
Amy Morck Thomas ◽  
Lynn M. Santarsiero ◽  
Eric R. Lutz ◽  
Todd D. Armstrong ◽  
Yi-Cheng Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cross Presentation ◽  
Cell Responses ◽  
Antigen Presenting

Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site.

Neutrophils efficiently cross-prime naive T cells in vivo

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2965-2973 ◽  
Author(s):  
Céline Beauvillain ◽  
Yves Delneste ◽  
Mari Scotet ◽  
Audrey Peres ◽  
Hugues Gascan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cross Presentation ◽  
Antigen Presenting

Abstract Neutrophils are professional phagocytes that migrate early, in high number, to the infection sites. Our study has analyzed how neutrophils cross-present antigens and influence CD8+ T-cell responses. By using highly purified neutrophils from peritoneal exudates and bone marrow, we have shown that neutrophils cross-present ovalbumin to a CD8+ T-cell hybridoma and to naive CD8+ T cells from OT1 transgenic mice. Cross-presentation by neutrophils was TAP and proteasome dependent and was as efficient as in macrophages. Moreover, it actually occurred earlier than in professional antigen-presenting cells. Peritoneal exudate neutrophils from mice injected intraperitoneally with ovalbumin also cross-presented ovalbumin, proving that neutrophils take up and present exogenous antigens into major histocompatibility complex I (MHC I) molecules in vivo. We then evaluated the in vivo influence of antigen cross-presentation by neutrophils on CD8+ T-cell response using β2-microglobulin-deficient mice transferred with OT1 CD8+ T cells and injected with ovalbumin-pulsed neutrophils. Four days after neutrophil injection, OT1 cells proliferated and expressed effector functions (IFN-γ production and cytolysis). They also responded efficiently to a rechallenge with ovalbumin-pulsed dendritic cells in CFA. These data are the first demonstration that neutrophils cross-prime CD8+ T cells in vivo and suggest that they may constitute, together with professional antigen-presenting cells, an attractive target to induce cytotoxic T cells in vaccines.

scholarly journals The Peripheral Deletion of Autoreactive CD8+ T Cells Induced by Cross-presentation of Self-antigens Involves Signaling through CD95 (Fas, Apo-1)

1998 ◽  
Vol 188 (2) ◽  
pp. 415-420 ◽  
Author(s):  
Christian Kurts ◽  
William R. Heath ◽  
Hiroshi Kosaka ◽  
Jacques F.A.P. Miller ◽  
Francis R. Carbone
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Wild Type ◽  
Cross Presentation ◽  
Insulin Promoter ◽  
I Cells ◽  
Self Antigens

Recently, we demonstrated that major histocompatibility complex class I–restricted cross-presentation of exogenous self-antigens can induce peripheral T cell tolerance by deletion of autoreactive CD8+ T cells. In these studies, naive ovalbumin (OVA)-specific CD8+ T cells from the transgenic line OT-I were injected into transgenic mice expressing membrane-bound OVA (mOVA) under the control of the rat insulin promoter (RIP) in pancreatic islets, kidney proximal tubules, and the thymus. Cross-presentation of tissue-derived OVA in the renal and pancreatic lymph nodes resulted in activation, proliferation, and then the deletion of OT-I cells. In this report, we investigated the molecular mechanisms underlying this form of T cell deletion. OT-I mice were crossed to tumor necrosis factor receptor 2 (TNFR2) knockout mice and to CD95 (Fas, Apo-1) deficient mutant lpr mice. Wild-type and TNFR2-deficient OT-I cells were activated and then deleted when transferred into RIP-mOVA mice, whereas CD95-deficient OT-I cells were not susceptible to deletion by cross-presentation. Furthermore, cross-presentation led to upregulation of the CD95 molecule on the surface of wild-type OT-I cells in vivo, consistent with the idea that this is linked to rendering autoreactive T cells susceptible to CD95-mediated signaling. This study represents the first evidence that CD95 is involved in the deletion of autoreactive CD8+ T cells in the whole animal.

scholarly journals Consequences of Cell Death

2000 ◽  
Vol 191 (3) ◽  
pp. 423-434 ◽  
Author(s):  
Birthe Sauter ◽  
Matthew L. Albert ◽  
Loise Francisco ◽  
Marie Larsson ◽  
Selin Somersan ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Apoptotic Cells ◽  
Antigenic Peptides ◽  
Tumor Cell Death ◽  
Cross Presentation ◽  
Necrotic Tumor ◽  
Antigen Presenting

Cell death by necrosis is typically associated with inflammation, in contrast to apoptosis. We have identified additional distinctions between the two types of death that occur at the level of dendritic cells (DCs) and which influence the induction of immunity. DCs must undergo changes termed maturation to act as potent antigen-presenting cells. Here, we investigated whether exposure to apoptotic or necrotic cells affected DC maturation. We found that immature DCs efficiently phagocytose a variety of apoptotic and necrotic tumor cells. However, only exposure to the latter induces maturation. The mature DCs express high levels of the DC-restricted markers CD83 and lysosome-associated membrane glycoprotein (DC-LAMP) and the costimulatory molecules CD40 and CD86. Furthermore, they develop into powerful stimulators of both CD4+ and CD8+ T cells. Cross-presentation of antigens to CD8+ T cells occurs after uptake of apoptotic cells. We demonstrate here that optimal cross-presentation of antigens from tumor cells requires two steps: phagocytosis of apoptotic cells by immature DCs, which provides antigenic peptides for major histocompatibility complex class I and class II presentation, and a maturation signal that is delivered by exposure to necrotic tumor cells, their supernatants, or standard maturation stimuli, e.g., monocyte-conditioned medium. Thus, DCs are able to distinguish two types of tumor cell death, with necrosis providing a control that is critical for the initiation of immunity.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

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

Blood ◽  
2012 ◽  
Vol 119 (6) ◽  
pp. 1407-1417 ◽  
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.

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

2002 ◽  
Vol 196 (6) ◽  
pp. 817-827 ◽  
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.

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

2015 ◽  
Vol 112 (47) ◽  
pp. 14664-14669 ◽  
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.

scholarly journals Analysis of complex formation of human recombinant hsp70 with tumor-associated peptides

2012 ◽  
Vol 58 (6) ◽  
pp. 651-661 ◽  
Author(s):  
V.A. Chernikov ◽  
N.V. Gorokhovets ◽  
L.V. Savvateeva ◽  
S.E. Severin
Keyword(s):  
Complex Formation ◽  
Antigenic Peptides ◽  
Cross Presentation ◽  
Hsp70 Family ◽  
Recombinant Hsp70 ◽  
Formation Method ◽  
Peptide Complexes ◽  
Antigen Presenting

Molecular chaperones of HSP70 family assists presentation of exogenous antigenic peptides by antigen-presenting cells (APC). HSP70-peptide complexes are powerful immunotherapeutic agents, which enhance cross-presentation of captured antigen in dendritic cells and macrophages. Several clinical trials have shown that HSP-based cancer vaccines possess good efficacy and safety. However, sometime it is impossible to isolate sufficient amount of vaccine. These make us to pay attention for recombinant HSP70-based vaccines and to optimize in vitro complex formation mechanism. Here we have investigated two human recombinant proteins HSP70HYB and HSC70. Optimal values of ADP concentration, pH, temperature and peptides excess are determined in this work. We have also shown that proposed complex formation method enriches eluted from HSP70-complexes peptide repertoire compared to in vivo assembled ones.

scholarly journals In vivo mRNA delivery to virus-specific T cells by light-induced ligand exchange of MHC class I antigen-presenting nanoparticles

2021 ◽  
Author(s):  
Fang-Yi Su ◽  
Qingyang Zhao ◽  
Shreyas N. Dahotre ◽  
Lena Gamboa ◽  
Swapnil Subhash Bawage ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Ligand Exchange ◽  
Uv Light ◽  
Class I ◽  
Multiple Populations ◽  
Peptide Epitopes ◽  
Peptide Exchange ◽  
Antigen Presenting

Simultaneous delivery of mRNA to multiple populations of antigen (Ag)-specific CD8+ T cells is challenging given the diversity of peptide epitopes and polymorphism of class I major histocompatibility complexes (MHCI). We developed Ag-presenting nanoparticles (APNs) for mRNA delivery using pMHCI molecules that were refolded with photocleavable peptides to allow rapid ligand exchange by UV light and site-specifically conjugated with a lipid tail for post-insertion into preformed mRNA lipid nanoparticles. Across different TCR transgenic mouse models (P14, OT-1, Pmel), UV-exchanged APNs bound and transfected their cognate Ag-specific CD8+ T cells equivalent to APNs produced using conventionally refolded pMHCI molecules. In mice infected with PR8 influenza, multiplexed delivery of UV-exchanged APNs against three immunodominant epitopes led to ~50% transfection of a VHH mRNA reporter in cognate Ag-specific CD8+ T cells. Our data shows that UV-mediated peptide exchange can be used to rapidly produce APNs for mRNA delivery to multiple populations of Ag-specific T cells in vivo.

Sign in / Sign up

Export Citation Format

Share Document