Biomedical subjects

Marina Cella

Publications and source records attributed to Marina Cella.

36 records · Page 2Linked to original sources

PubMed2004

Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation.

Signal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPalpha binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPbeta1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPbeta2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.

CD47 Antigen↗

PubMed2004

Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK cell cytotoxicity.

Natural killer (NK) cells express multiple activating receptors that initiate signaling cascades through DAP10- or immunoreceptor tyrosine-based activation motif-containing adapters, including DAP12 and FcRgamma. Among downstream signaling mediators, the guanine nucleotide exchange factor Vav1 carries out a key role in activation. However, whether Vav1 regulates only some or all NK cell-activating pathways is matter of debate. It is also possible that two other Vav family molecules, Vav2 and Vav3, are involved in NK cell activation. Here, we examine the relative contribution of each of these exchange factors to NK cell-mediated cytotoxicity using mice lacking one, two, or all three Vav proteins. We found that Vav1 deficiency is sufficient to disrupt DAP10-mediated cytotoxicity, whereas lack of Vav2 and Vav3 profoundly impairs FcRgamma- and DAP12-mediated cytotoxicity. Our results provide evidence that these three Vav proteins function specifically in distinct pathways that trigger NK cell cytotoxicity.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155).

The poliovirus receptor (PVR) belongs to a large family of Ig molecules called nectins and nectin-like proteins, which mediate cell-cell adhesion, cell migration, and serve as entry receptors for viruses. It has been recently shown that human NK cells recognize PVR through the receptor DNAM-1, which triggers NK cell stimulation in association with beta(2) integrin. In this study, we show that NK cells recognize PVR through an additional receptor, CD96, or T cell-activated increased late expression (Tactile). CD96 promotes NK cell adhesion to target cells expressing PVR, stimulates cytotoxicity of activated NK cells, and mediates acquisition of PVR from target cells. Thus, NK cells have evolved a dual receptor system that recognizes nectins and nectin-like molecules on target cells and mediates NK cell adhesion and triggering of effector functions. As PVR is highly expressed in certain tumors, this receptor system may be critical for NK cell recognition of tumors.

Animals↗

PubMed2004

Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells.

In humans, the type I interferon (IFN) family consists of 13 IFN-alpha subtypes, IFN-beta and IFN-omicron the newly discovered IFN-like family consists of IFN-lambda1, -lambda2 and -lambda3. We have investigated the expression of type I and lambda IFN genes following virus infections or Toll-like receptor (TLR) triggering in monocyte-derived DC (MDDC) and plasmacytoid DC (pDC). We found that all IFN-alpha, -beta, -omicron and -lambda subtypes are expressed in influenza-virus-infected MDDC or pDC. Conversely, differential type I IFN gene transcription was induced in MDDC and pDC stimulated by specific TLR agonists. TLR-9 stimulation by CpG DNA induced the expression of all IFN-alpha, -beta, -omicron and -lambda subtypes in pDC, whereas TLR-4 stimulation by LPS, or TLR-3 stimulation by poly I:C, induced only IFN-beta and IFN-lambda gene expression in MDDC. The expression pattern of IFN regulatory factor (IRF)-5 and IRF-7 in MDDC and pDC was also determined. IRF-5 was constitutively expressed in the two DC subsets whereas IRF-7 was constitutive in pDC but its expression was induced along MDDC maturation. Overall, our data indicate that the coordinated expression of IFN-lambda with IFN-beta would be of crucial importance for the maturation of DC.

Cell Line↗

PubMed2003

A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-alpha.

Natural interferon (IFN)-producing cells (IPCs) recognize certain viruses and DNA containing deoxycytidylate-phosphatedeoxyguanylate (CpG) motifs through the toll-like receptor (TLR) 9, resulting in secretion of IFN-alpha, interleukin 12 (IL-12), and proinflammatory chemokines. Human IPCs are found mainly in inflamed lymph nodes, where they are presumably recruited from the blood to activate both innate and adaptive responses to microbial infections. Demonstrating IPC recruitment and function in murine infection models has been difficult because multiple antibodies are required to distinguish IPCs from other immune cells and very few IPCs can be recovered from lymph nodes. Here we describe a monoclonal antibody (mAb) that exclusively detects murine IPCs in all lymphoid organs under both normal and inflammatory conditions. Using this antibody, we demonstrate that IPCs are normally present in the T-cell zone of lymph nodes and spleen and that inoculation of peripheral tissues with inflammatory stimuli triggers recruitment of IPC into sentinel lymph nodes, whether the stimuli are able to directly stimulate IPCs through TLR or not. Remarkably, we show that incubation of IPCs with the antibody in vitro or administration of the antibody in vivo dramatically reduce secretion of IFN-alpha in response to CpG DNA without causing IPC depletion. Thus, the antibody identifies an IPC-specific surface molecule that, when engaged, inhibits IFN-alpha secretion.

Animals↗

PubMed2003

Impaired differentiation of osteoclasts in TREM-2-deficient individuals.

TREM-2 is an immunoglobulin-like cell surface receptor associated with DAP12/KARAP that activates monocyte-derived dendritic cells (DCs) in vitro. Recently, it has been shown that genetic defects of human DAP12/KARAP and TREM-2 result in a rare syndrome characterized by bone cysts and presenile dementia called Nasu-Hakola disease. This observation suggests that TREM-2 may function in myeloid cells other than DCs, most probably osteoclasts (OCs) and microglial cells, which are involved in bone modeling and brain function. Consistent with this prediction, here we show that OC differentiation is dramatically arrested in TREM-2-deficient patients, resulting in large aggregates of immature OCs that exhibit impaired bone resorptive activity. These results demonstrate a critical role for TREM-2 in the differentiation of mononuclear myeloid precursors into functional multinucleated OCs.

Actins↗

PubMed2003

Dendritic cells process and present antigens across a range of maturation states.

We isolated dendritic cells (DC) from lymphoid organs of mice bearing a transgene for a membrane-bound form of the model protein hen egg white lysozyme (HEL). DC from the spleen had a lower representation of costimulatory molecules and class II MHC molecules than those isolated from lymph nodes and thymi. Splenic DC were capable of further maturation by in vivo treatment of mice with LPS. The immature DC from spleen processed HEL and displayed the chemically dominant epitope as evidenced by FACS analysis. These immature DC also presented this epitope to CD4(+) T cells. Splenic DC from another transgenic mouse (ML-5) containing serum HEL also showed the ability to process and present Ag despite low levels of circulating HEL. In vitro-derived DC from the bone marrow (bone marrow-derived DC) of mHEL mice also displayed immature to mature features and in both cases displayed HEL peptides as well as SDS-stable MHC class II molecules. Immature bone marrow-derived DC also processed exogenous HEL. We conclude that the DC sets normally found in tissue show a scale of maturation features but even the most immature process and present peptides by MHC class II molecules.

Animals↗

PubMed2003

Interferon-producing cells fail to induce proliferation of naive T cells but can promote expansion and T helper 1 differentiation of antigen-experienced unpolarized T cells.

Interferon-producing cells (IPCs) secrete high levels of type I interferon in response to certain viruses. The lack of lineage markers, the expression of major histocompatibility complex (MHC) class II and the capacity to stimulate allogeneic T cells have led these cells to be classified as a subset of dendritic cells (DCs), called plasmacytoid DCs (PDCs). However, the role of IPCs/PDCs in initiating primary immune responses remains elusive. Here we examined the antigen presenting capacity of murine IPCs in antigen specific systems. While CD8alpha+ and CD11b+ DCs induced logarithmic expansion of naive CD4 and CD8 T cells, without conferring T helper commitment at a first encounter, primary IPCs lacked the ability to stimulate naive T cells. However, when antigen-experienced, nonpolarized T cells expanded by classical DC subsets, were restimulated by IPCs, they proliferated and produced high amounts of IFN-gamma. These data indicate that IPCs can effectively stimulate preactivated or memory-type T cells and exert an immune-regulatory role. They also suggest that expansion of naive T cells and acquisition of effector function during antigen-specific T cell responses may involve different antigen-presenting cell (APC) types. Independent and coordinated control of T cell proliferation and differentiation would provide the immune system with greater flexibility in regulating immune responses.

Animals↗

PubMed2003

The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration.

Indinavir (IDV) is a protease inhibitor that successfully suppresses HIV-1 replication as part of anti-retroviral therapy. There is evidence to suggest that IDV may also act non-specifically upon host proteases. In this study we investigated whether IDV could modulate protease-dependent molecules involved in dendritic cell (DC) migration - a pivotal process in immunoregulation. Human monocyte-derived DC were exposed to IDV (IDV-DC) and transendothelial migration (TEM) to inflammatory chemokines was determined. TEM of IDV-DC was significantly impaired compared to non-treated DC (p<0.01). Phenotypic analysis revealed that IDV-DC had reduced DC-SIGN expression, correlating with reduced adhesion to immobilized ICAM-2. Nevertheless, the reduction in migration following exposure to IDV could not be fully attributable to DC-SIGN interactions alone. Investigation of IDV-DC interactions with the underlying matrix protein, fibronectin, demonstrated that IDV significantly impaired DC binding to immobilized fibronectin (p<0.01). IDV appeared to act upon VLA-4 and VLA-5 since addition of antagonist monoclonal antibodies (mAb) similarly reduced adhesion of non-treated DC to fibronectin. Combined blockade of DC using anti-VLA-4, VLA-5 and anti-DC-SIGN mAb inhibited TEM to a similar extent as IDV. Our results strongly suggest that IDV inhibits host proteases necessary for DC migration and may, therefore, affect DC immunoregulation in HIV-1-infected patients.

Antigens, CD↗

PubMed2003

Plasmacytoid dendritic cells prime IFN-gamma-secreting melanoma-specific CD8 lymphocytes and are found in primary melanoma lesions.

Plasmacytoid dendritic cells (PDC) are a small population of leukocytes specialized in the production of type I IFN. It has been shown that PDC have a potent T cell stimulatory capacity in allogeneic mixed lymphocyte reaction, However, their role in initiating primary immune responses remains elusive. We report that blood PDC efficiently prime naive CD8(+) lymphocytes specific for the melan-A(26-35) epitope to become IFN-gamma producing cells in vitro. In addition, we found that CD40L-stimulated PDC induce expression on primed melan-A-specific T cells of cutaneous lymphocyte antigen and L-selectin (CD62L), homing receptors that allow the migration of effector cells to the inflamed skin. Finally, we show that PDC can be found in the peri-tumoral area of most primary cutaneous melanomas in vivo and that type I IFN-containing supernatants derived from PDC increase melanoma cell surface expression of CD95 and MHC class I and class II molecules in vitro. Our results suggest a new immunomodulatory role for tissue infiltrating PDC, which may prime tumor-specific T cell responses and affect tumor growth via soluble factors.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2003

Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas.

The present study has analysed the distribution and phenotype of dendritic cells (DCs) in primary cutaneous melanomas and sentinel lymph nodes by immunohistochemistry. In primary melanomas, an increase of DCs was found in the epidermis and the peritumoural area. Intraepidermal DCs were mostly CD1a(+)/Langerin(+) Langerhans cells. Peritumoural DCs included a large population of DC-SIGN(+)/mannose-receptor(+)/CD1a(-) DCs, a small subset of CD1a(+) DCs, and, remarkably, plasmacytoid monocytes/plasmacytoid DCs (PM/PDCs). The PM/PDCs, most likely recruited by SDF-1 secreted by melanoma cells, produced type I interferon (IFN-I), but the expression of the IFN-alpha inducible protein MxA was extremely variable and very limited in the majority of cases. All DC subsets were predominantly immature. The peritumoural area also contained a minor subset of mature CD1a(+) DCs. However, the small amount of local interleukin (IL)-12 p40 mRNA and the naïve phenotype of 20-50% of peritumoural T-lymphocytes are consistent with poor T-cell stimulation or erroneous recruitment. In sentinel lymph nodes, notable expansion of mature CD1a(+)/Langerin(+) DCs was observed. The paucity of intratumoural DCs and the predominant immature phenotype of peritumoural dermal DCs indicate defective maturation of primary cutaneous melanoma-associated DCs, resulting in lack of T-cell priming. These results may explain why melanoma cells grow despite the presence of infiltrating immune cells.

Aged↗

PubMed2002

CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity.

Natural killer (NK) cells are innate lymphocytes that provide cytokines critical for early host defense against pathogens. One subset of human NK cells (CD56(bright)) constitutively expresses the high-affinity interleukin 2 (IL-2) receptor and produces immunoregulatory cytokines. Here, we demonstrate that CD56(bright) NK cells are present in human lymph nodes and that endogenous T cell-derived IL-2, acting through the NK high-affinity IL-2 receptor, costimulates CD56(bright) NK cells to secrete IFN-gamma. Thus, adaptive immunoregulators influence innate cytokine production, which in turn may influence the developing antigen-specific immune response. These data show a dynamic interaction between innate and adaptive human lymphocytes and emphasize the importance of studying interactions between immune components to understand the immune response as a whole.

Adult↗

PubMed2002

IFN-producing cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation.

Human natural IFN-producing cells (IPC) circulate in the blood and cluster in chronically inflamed lymph nodes around high endothelial venules (HEV). Although L-selectin, CXCR4, and CCR7 are recognized as critical IPC homing mediators, the role of CXCR3 is unclear, since IPC do not respond to CXCR3 ligands in vitro. In this study, we show that migration of murine and human IPC to CXCR3 ligands in vitro requires engagement of CXCR4 by CXCL12. We also demonstrate that CXCL12 is present in human HEV in vivo. Moreover, after interaction with pathogenic stimuli, murine and human IPC secrete high levels of inflammatory chemokines. Thus, IPC migration into inflamed lymph nodes may be initially mediated by L-selectin, CXCL12, and CXCR3 ligands. Upon pathogen encounter, IPC positioning within the lymph node may be further directed by CCR7 and IPC secretion of inflammatory chemokines may attract other IPC, promoting cluster formation in lymph nodes.

Animals↗

PubMed2002

NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation.

NKG2D is a receptor on natural killer (NK) cells and cytotoxic T lymphocytes that binds major histocompatibility complex (MHC) class I-like ligands expressed primarily on virally infected and neoplastic cells. In vitro studies indicate that NKG2D provides costimulation through an associated adapter, DAP10, which recruits phosphatidylinositol-3 kinase. Here we show that in DAP10-deficient mice, CD8+ T cells lack NKG2D expression and are incapable of mounting tumor-specific responses. However, DAP10-deficient NK cells express a functional NKG2D receptor due to the association of NKG2D with another adapter molecule, DAP12 (also known as KARAP), which recruits protein tyrosine kinases. Thus, NKG2D is a versatile receptor that, depending on the availability of adapter partners, mediates costimulation in T cells and/or activation in NK cells.

Adaptor Proteins, Signal Transducing↗

PubMed2002

An unusual Fc receptor-related protein expressed in human centroblasts.

Here, we report the identification of Fc receptor homolog expressed in B cells (FREB), a unique B cell-specific molecule that is distantly related to FcgammaRI (receptor I for the Fc fragment of IgG) and is encoded on human chromosome 1q, within the FcgammaR gene region. FREB has an intracellular distribution and lacks a canonical transmembrane domain. In addition, FREB lacks bona fide Fc fragment binding regions and does not bind immunoglobulins. By using specific monoclonal antibodies, we show that FREB is preferentially expressed in germinal center centroblasts, which undergo affinity maturation and class-switch recombination. Together, these characteristics indicate that FREB may have a unique role in B cell differentiation. FREB is also expressed in some B cell lymphomas, most of which have centroblast origin. Remarkably, FREB is expressed in a subset of diffuse large B cell lymphomas, providing a unique marker for the characterization of this B cell malignancy.

Amino Acid Sequence↗

PubMed2002

Virus-induced interferon alpha production by a dendritic cell subset in the absence of feedback signaling in vivo.

An effective type I interferon (IFN-alpha/beta) response is critical for the control of many viral infections. Here we show that in vesicular stomatitis virus (VSV)-infected mouse embryonic fibroblasts (MEFs) the production of IFN-alpha is dependent on type I IFN receptor (IFNAR) triggering, whereas in infected mice early IFN-alpha production is IFNAR independent. In VSV-infected mice type I IFN is produced by few cells located in the marginal zone of the spleen. Unlike other dendritic cell (DC) subsets, FACS((R))-sorted CD11c(int)CD11b(-)GR-1(+) DCs show high IFN-alpha expression, irrespective of whether they were isolated from VSV-infected IFNAR-competent or -deficient mice. Thus, VSV preferentially activates a specialized DC subset presumably located in the marginal zone to produce high-level IFN-alpha largely independent of IFNAR feedback signaling.

Animals↗

PubMed2002

Interferon-producing cells: on the front line in immune responses against pathogens.

Interferon-producing cells (IPC) constitute a small population of leukocytes that secrete high levels of type I interferons in response to viruses. Although human IPC have been known for almost two decades, murine IPC have been identified only recently. Furthermore, it has been shown that IPC correspond to the enigmatic 'plasmacytoid cells' identified in human lymph nodes during infections. These breakthroughs have brought IPC to the attention of immunologists for their role in innate immunity and in shaping T cell responses. Here we review recent progress and outstanding questions in the field.

Animals↗

PubMed2002

Capture and transfer of simian immunodeficiency virus by macaque dendritic cells is enhanced by DC-SIGN.

Dendritic cells (DCs) are among the first cells encountered by human and simian immunodeficiency virus (HIV and SIV) following mucosal infection. Because these cells efficiently capture and transmit virus to T cells, they may play a major role in mediating HIV and SIV infection. Recently, a C-type lectin protein present on DCs, DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), was shown to efficiently bind and present HIV and SIV to CD4(+), coreceptor-positive cells in trans. However, the significance of DC-SIGN for virus transmission and pathogenesis in vivo remains unclear. Because SIV infection of macaques may represent the best model to study the importance of DC-SIGN in HIV infection, we cloned and characterized pig-tailed macaque DC-SIGN and generated monoclonal antibodies (MAbs) against it. We demonstrate that, like human DC-SIGN, pig-tailed macaque DC-SIGN (ptDC-SIGN) is expressed on DCs and macrophages but not on monocytes, T cells, or B cells. Moderate levels of ptDC-SIGN expression were detected on the surface of DCs, and low-level expression was found on macrophages. Additionally, we show that ptDC-SIGN efficiently binds and transmits replication-competent SIVmne variants to CD4(+), coreceptor-positive cells. Moreover, transmission of virus between pig-tailed macaque DCs and CD4(+) T cells is largely ptDC-SIGN dependent. Interestingly, MAbs directed against ptDC-SIGN vary in the capacity to block transmission of different SIVmne variants. These data demonstrate that ptDC-SIGN plays a central role in transmitting virus from macaque DCs to T cells, and they suggest that SIVmne variants may differ in their interactions with ptDC-SIGN. Thus, SIVmne infection of pig-tailed macaques may provide an opportunity to investigate the significance of DC-SIGN in primate lentiviral infections.

Animals↗