Alain Vicari | TU Kaiserslautern (original) (raw)
Papers by Alain Vicari
International Immunology, 1996
Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by t... more Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by the severe T lymphopenia observed in IL-7-deficient mice. We recently reported that IL-7 preferentially promotes the in vitro expansion of a discrete MHC class I-dependent lymphocyte subset comprising both CD4+ and CD4-CD8- TCR alpha beta + cells bearing several NK cells markers such NK1.1 and Ly-49. These T cells, designated as NK1+ T cells, have the unique property among thymocytes of producing large amounts of IL-4 upon primary stimulation via the TCR. We have further demonstrated that thymic NK1+ T cells of non-obese diabetic (NOD) mice, a spontaneous model of autoimmune type I diabetes, are markedly deficient in maturation both quantitatively and functionally (IL-4 production). In the present experiments, the addition of exogenous IL-7 completely restored IL-4 production by anti-TCR alpha beta-stimulated mature (HSA-CD8-) thymocytes in NOD mice. A short 2 h preincubation with IL-7 was sufficient to restore both the expression of IL-4 mRNA and IL-4 production capacity. This was related to a direct effect on NK1+ thymocytes since: (i) the effect of IL-7 was restricted to the non-mainstream MEL-14- 3G11- TCR alpha beta + subset which mostly concentrates the IL-4-producing capacity and (ii) IL-7 did not restore IL-4 production in class I-deficient mice which lack the NK1+ T cell subset. Importantly, this activity of IL-7 on NK1+ T cells was also demonstrated in non-autoimmune strains of mice. These results were extended in vivo by showing that the IL-7 treatment significantly increased the anti-CD3 triggered IL-4 production by NK1+ T spleen cells. These findings confirm the role of IL-7 in NK1+ T cell maturation and suggest that the NK1+ T cell defect in NOD mice could be related to insufficient intrathymic IL-7 bioavailability.
Proceedings of The National Academy of Sciences, 1996
Escherichia coli selenophosphate synthetase (SPS, the selD gene product) catalyzes the production... more Escherichia coli selenophosphate synthetase (SPS, the selD gene product) catalyzes the production of monoselenophosphate, the selenium donor compound required for synthesis of selenocysteine (Sec) and seleno-tRNAs. We report the molecular cloning of human and mouse homologs of the selD gene, designated Sps2, which contains an in-frame TGA codon at a site corresponding to the enzyme's putative active site. These sequences allow the identification of selD gene homologs in the genomes of the bacterium Haemophilus influenzae and the archaeon Methanococcus jannaschii, which had been previously misinterpreted due to their in-frame TGA codon. Sps2 mRNA levels are elevated in organs previously implicated in the synthesis of selenoproteins and in active sites of blood cell development. In addition, we show that Sps2 mRNA is up-regulated upon activation of T lymphocytes and have mapped the Sps2 gene to mouse chromosome 7. Using the mouse gene isolated from the hematopoietic cell line FDCPmixA4, we devised a construct for protein expression that results in the insertion of a FLAG tag sequence at the N terminus of the SPS2 protein. This strategy allowed us to document the readthrough of the in-frame TGA codon and the incorporation of 75Se into SPS2. These results suggest the existence of an autoregulatory mechanism involving the incorporation of Sec into SPS2 that might be relevant to blood cell biology. This mechanism is likely to have been present in ancient life forms and conserved in a variety of living organisms from all domains of life.
Immunity, 2006
The nature of dendritic cell(s) (DC[s]) that conditions efficient in vivo priming of CD8 + CTL af... more The nature of dendritic cell(s) (DC[s]) that conditions efficient in vivo priming of CD8 + CTL after immunization via epithelial tissues remains largely unknown. Here, we show that myeloid DCs rapidly recruited by adjuvants into the buccal mucosa or skin are essential for CD8 + T cell crosspriming. Recruitment of circulating DC precursors, including Gr1 + monocytes, precedes the sequential accumulation of CD11c + MHC class II + DCs in dermis and epithelium via a CCR6/ CCL20-dependent mechanism. Remarkably, a defect in CCR6, local neutralization of CCL20, or depletion of monocytes prevents in vivo priming of CD8 + CTL against an innocuous protein antigen administered with adjuvant. In addition, transfer of CCR6-sufficient Gr1 + monocytes restores CD8 + T cell priming in CCR6 º/º mice via a direct Ag presentation mechanism. Thus, newly recruited DCs likely derived from circulating monocytes are responsible for efficient crosspriming of CD8 + CTL after mucosal or skin immunization.
DC function as sentinels of the immune system. They traffic from the blood to the tissues where, ... more DC function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. They then leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. This suggestive link between DC traffic pattern and functions led to the investigation of the chemokine responsiveness of DC during their development and maturation. These studies have shown that immature and mature DC are not recruited by the same chemokines. Immature DC respond to many CC-and CXC-chemokines (MIP-1␣, MIP-1, MIP-5, MCP-3, MCP-4, RANTES, TECK, and SDF-1) and in particular to MIP-3␣/LARC, which acts through CCR6, a receptor mainly expressed in DC and lymphocytes. Like most other chemokines acting on immature DC, MIP-3␣ is inducible on inflammatory stimuli. In contrast, mature DC have lost their responsiveness to most of these chemokines through receptor down-regulation or desensitization, but acquired responsiveness to MIP-3/ELC and 6Ckine/SLC as a consequence of CCR7 up-regulation. MIP-3␣ mRNA is only detected within inflamed epithelial crypts of tonsils, the site of antigen entry known to be infiltrated by immature DC, whereas MIP-3 and 6Ckine are specifically expressed in the T cell-rich areas where mature IDC home. These observations suggest a role for chemokines induced on inflammation such as MIP-3␣ in recruitment of immature DC at the site of injury and a role for MIP-3/6Ckine in accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node. A better understanding of the regulation of DC trafficking might offer new opportunities of therapeutic interventions to suppress or stimulate the immune response. J. Leukoc. Biol. 66: 252-262; 1999.
Springer Seminars in Immunopathology, 2000
DC (dendritic cells) represent an heterogeneous family of cells which function as sentinels of th... more DC (dendritic cells) represent an heterogeneous family of cells which function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. Then, following inflammatory stimuli, they leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. The key role of DC migration in their sentinel function led to the investigation of the chemokine responsiveness of DC populations during their development and maturation. These studies have shown that immature DC respond to many CC and CXC chemokines (MIP-lα, MIP-iβ, MIP-3α, MIP-5, MCP-3, MCP-4, RANTES, TECK and SDF-1) which are inducible upon inflammatory stimuli. Importantly, each immature DC population displays a unique spectrum of chemokine responsiveness. For examples, Langerhans cells migrate selectively to MIP-3α (via CCR6), blood CDllc+ DC to MCP chemokines (via CCR2), monocytes derived-DC respond to MIP-lα/β (via CCR1 and CCR5), while blood CDllc- DC precursors do not respond to any of these chemokines. All these chemokines are inducible upon inflammatory stimuli, in particular MIP-3α, which is only detected within inflamed epithelium, a site of antigen entry known to be infiltrated by immature DC. In contrast to immature DC, mature DC lose their responsiveness to most of these inflammatory chemokines through receptor down-regulation or desensitization, but acquire responsiveness to ELC/MIP-3β and SLCASCkine as a consequence of CCR7 up-regulation. ELC/MIP-3(3 and SLC/6Ckine are specifically expressed in the T-cell-rich areas where mature DC home to become interdigitating DC. Altogether, these observations suggest that the inflammatory chemokines secreted at the site of pathogen invasion will determine the DC subset recruited and will influence the class of the immune response initiated. In contrast, MIP-3β/6Ckine have a determinant role in the accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node, as illustrated by recent observations in mice deficient for CCR7 or SLC/6Ckine. A better understanding of the regulation of DC trafficking might offer new opportunities of therapeutic interventions to suppress, stimulate or deviate the immune response.
DCs (dendritic cells) function as sentinels of the immune system. They traffic from the blood to ... more DCs (dendritic cells) function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. They then leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. This suggestive link between DC traffic pattern and functions led us to investigate the chemokine responsiveness of DCs during their development and maturation. DCs were differentiated either from CD34 ϩ hematopoietic progenitor cells (HPCs) cultured with granulocyte/macrophage colony-stimulating factor (GM-CSF) plus tumor necrosis factor (TNF)-␣ or from monocytes cultured with GM-CSF plus interleukin 4. Immature DCs derived from CD34 ϩ HPCs migrate most vigorously in response to macrophage inflammatory protein (MIP)-3 ␣ , but also to MIP-1 ␣ and RANTES (regulated on activation, normal T cell expressed and secreted). Upon maturation, induced by either TNF-␣ , lipopolysaccharide, or CD40L, DCs lose their response to these three chemokines when they acquire a sustained responsiveness to a single other chemokine, MIP-3  . CC chemokine receptor (CCR)6 and CCR7 are the only known receptors for MIP-3 ␣ and MIP-3  , respectively. The observation that CCR6 mRNA expression decreases progressively as DCs mature, whereas CCR7 mRNA expression is sharply upregulated, provides a likely explanation for the changes in chemokine responsiveness. Similarly, MIP-3  responsiveness and CCR7 expression are induced upon maturation of monocytederived DCs. Furthermore, the chemotactic response to MIP-3  is also acquired by CD11c ϩ DCs isolated from blood after spontaneous maturation. Finally, detection by in situ hybridization of MIP-3 ␣ mRNA only within inflamed epithelial crypts of tonsils, and of MIP-3  mRNA specifically in T cell-rich areas, suggests a role for MIP-3 ␣ /CCR6 in recruitment of immature DCs at site of injury and for MIP-3  /CCR7 in accumulation of antigen-loaded mature DCs in T cell-rich areas.
Dendritic cells (DCs) form a network comprising different populations that initiate and different... more Dendritic cells (DCs) form a network comprising different populations that initiate and differentially regulate immune responses. Langerhans cells (LCs) represent a unique population of DCs colonizing epithelium, and we present here observations suggesting that macrophage inflammatory protein (MIP)-3 ␣ plays a central role in LC precursor recruitment into the epithelium during inflammation. (a) Among DC populations, MIP-3 ␣ was the most potent chemokine inducing the selective migration of in vitro-generated CD34 ϩ hematopoietic progenitor cell-derived LC precursors and skin LCs in accordance with the restricted MIP-3 ␣ receptor (CC chemokine receptor 6) expression to these cells. (b) MIP-3 ␣ was mainly produced by epithelial cells, and the migration of LC precursors induced by the supernatant of activated skin keratinocytes was completely blocked with an antibody against MIP-3 ␣ . (c) In vivo, MIP-3 ␣ was selectively produced at sites of inflammation as illustrated in tonsils and lesional psoriatic skin where MIP-3 ␣ upregulation appeared associated with an increase in LC turnover. (d) Finally, the secretion of MIP-3 ␣ was strongly upregulated by cells of epithelial origin after inflammatory stimuli (interleukin 1  plus tumor necrosis factor ␣ ) or T cell signals. Results of this study suggest a major role of MIP-3 ␣ in epithelial colonization by LCs under inflammatory conditions and immune disorders, and might open new ways to control epithelial immunity.
European Journal of Immunology, 2002
To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to trav... more To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to traverse the endothelial barrier, progress through the tissue (i.e. dermis) and cross the dermoepithelial junction (basal membrane). In the present study, we demonstrate that (1) circulating blood DC and monocytes express high levels of CCR2 and primarily respond to monocyte chemotactic protein (MCP) and not to macrophage inflammatory protein (MIP)-3 § / CCL20; (2) while the CD34 + hematopoietic progenitor cells (HPC)-derived CD1a + precursors committed to Langerhans cell differentiation primarily respond to MIP-3 § /CCL20, the HPCderived CD14 + precursors respond to both MCP and MIP-3 § /CCL20; (3) in concordance with the sequential expression of CCR2 and CCR6, the HPC-derived CD14 + precursors initially acquire the ability to migrate in response to MCP-4/CCL13 and subsequently in response to MIP-3 § /CCL20; and (4) in vivo, in inflamed epithelium, MCP-4/CCL13 and MIP-3 § /CCL20 form complementary gradients, with MCP-4/CCL13 expressed in basal epithelial cells at the contact of blood vessels, while MIP-3 § /CCL20 expression is restricted to epithelial cells bordering the external milieu. These observations suggest that the recruitment of DC to the site of infection is controlled by the sequential action of different chemokines: (i) CCR2 + circulating DC or DC precursors are mobilized into the tissue via the expression of MCP by cells lining blood vessels, and (ii) these cells traffic from the tissue to the site of pathogen invasion via the production of MIP-3 § /CL20 by epithelial cells and the up-regulation of CCR6 in response to the tissue environment.
and plasmacytoid DC (pDCs) has been suggested to influence the type of immune response induced by... more and plasmacytoid DC (pDCs) has been suggested to influence the type of immune response induced by microbial pathogens. In this study we show that, in vivo, cDCs and pDCs are equally activated by TLR4, -7, and -9 ligands. Type I interferon (IFN) was important for pDC activation in vivo in response to all three TLR ligands, whereas cDCs required type I IFN signaling only for TLR9-and partially for TLR7-mediated activation. Although TLR ligands induced in situ migration of spleen cDC into the T cell area, spleen pDCs formed clusters in the marginal zone and in the outer T cell area 6 h after injection of TLR9 and TLR7 ligands, respectively. In vivo treatment with TLR9 ligands decreased pDC ability to migrate ex vivo in response to IFN-induced CXCR3 ligands and increased their response to CCR7 ligands. Unlike cDCs, the migration pattern of pDCs required type I IFN for induction of CXCR3 ligands and responsiveness to CCR7 ligands. These data demonstrate that mouse pDCs differ from cDCs in the in vivo response to TLR ligands, in terms of pattern and type I IFN requirement for activation and migration.
Transplantation, 2002
Dendritic cells (DC) are a heterogeneous family of cells that function as sentinels of the immune... more Dendritic cells (DC) are a heterogeneous family of cells that function as sentinels of the immune system. This article summarizes observations suggesting that inflammatory chemokines secreted at the site of pathogen invasion determine the DC subset recruited and influence the class of the immune response initiated. Langerhans cells are selectively recruited by MIP-3alpha/CCL20. In contrast, CCR7 ligands have a key role in the accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node. Improved understanding of the regulation of DC trafficking might offer new opportunities for therapeutic interventions to control immune responses.
European Journal of Immunology, 2002
To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to trav... more To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to traverse the endothelial barrier, progress through the tissue (i.e. dermis) and cross the dermoepithelial junction (basal membrane). In the present study, we demonstrate that (1) circulating blood DC and monocytes express high levels of CCR2 and primarily respond to monocyte chemotactic protein (MCP) and not to macrophage inflammatory protein (MIP)-3 § / CCL20; (2) while the CD34 + hematopoietic progenitor cells (HPC)-derived CD1a + precursors committed to Langerhans cell differentiation primarily respond to MIP-3 § /CCL20, the HPCderived CD14 + precursors respond to both MCP and MIP-3 § /CCL20; (3) in concordance with the sequential expression of CCR2 and CCR6, the HPC-derived CD14 + precursors initially acquire the ability to migrate in response to MCP-4/CCL13 and subsequently in response to MIP-3 § /CCL20; and (4) in vivo, in inflamed epithelium, MCP-4/CCL13 and MIP-3 § /CCL20 form complementary gradients, with MCP-4/CCL13 expressed in basal epithelial cells at the contact of blood vessels, while MIP-3 § /CCL20 expression is restricted to epithelial cells bordering the external milieu. These observations suggest that the recruitment of DC to the site of infection is controlled by the sequential action of different chemokines: (i) CCR2 + circulating DC or DC precursors are mobilized into the tissue via the expression of MCP by cells lining blood vessels, and (ii) these cells traffic from the tissue to the site of pathogen invasion via the production of MIP-3 § /CL20 by epithelial cells and the up-regulation of CCR6 in response to the tissue environment.
Nature Immunology, 2001
We show here that mouse interferon-alpha (IFN-alpha)-producing cells (mIPCs) are a unique subset ... more We show here that mouse interferon-alpha (IFN-alpha)-producing cells (mIPCs) are a unique subset of immature antigen-presenting cells (APCs) that secrete IFN-alpha upon stimulation with viruses. mIPCs have a plasmacytoid morphology, can be stained with an antibody to Ly6G and Ly6C (anti-Ly6G/C) and are Ly6C+B220+CD11cloCD4+; unlike other dendritic cell subsets, however, they do not express CD8alpha or CD11b. Although mIPCs undergo apoptosis in vitro, stimulation with viruses, IFN-alpha or CpG oligonucleotides enhanced their survival and T cell stimulatory activity. In vivo, mIPCs were the main producers of IFN-alpha in cytomegalovirus-infected mice, as depletion of Ly6G+/C+ cells abrogated IFN-alpha production. mIPCs produced interleukin 12 (IL-12) in response to viruses and CpG oligodeoxynucleotides, but not bacterial products. Although different pathogens can selectively engage various APC subsets for IL-12 production, IFN-alpha production is restricted to mIPCs' response to viral infection.
Immunological Reviews, 2008
Summary: Interleukin-10 (IL-10) is a cytokine with broad anti-inflammatory properties by its supp... more Summary: Interleukin-10 (IL-10) is a cytokine with broad anti-inflammatory properties by its suppression of both macrophage and dendritic cell function, including antigen-presenting cell function and the production of proinflammatory cytokines. This can result subsequently in the feedback regulation of both T-helper 1 (Th1)-type and Th2-type responses. This review discusses the potential use of IL-10 or agents that induce IL-10 as potential anti-inflammatory therapies in inflammatory diseases. Although IL-10-deficient mice develop colitis in the presence of normal gut flora and clear certain intracellular pathogens more efficiently, this is often accompanied by immunopathology, which can be lethal to the host. This reinforces the anti-inflammatory properties of IL-10, although it should be noted that as discussed below, IL-10 can also promote B-cell and other immune responses under particular settings. A penalty of its role to limit the immune and inflammatory responses to pathogens and prevent damage to the host is that high or dysregulated levels of IL-10 may result in chronic infection. Thus, antagonists of IL-10 show great potential as adjuvants in preventative or therapeutic vaccines against chronic infection or cancer. This article reviews basic published studies on IL-10, which may lead to potential uses of IL-10 or its antagonists in human disease.
Cladribine (2-chloro-2&am... more Cladribine (2-chloro-2'-deoxyadenosine) is a purine nucleoside analogue (PNA) which causes targeted and sustained reduction of peripheral lymphocyte counts. Cladribine tablets produced significant treatment benefit for patients with relapsing-remitting multiple sclerosis in the phase 3 CLARITY study. In addition to the well-characterised cell-specific phosphorylation of PNAs responsible for lymphocyte reduction, the mode of action of cladribine may encompass distinct activities contributing to its overall effects on the immune system. Here we demonstrate that clinically relevant concentrations of cladribine also inhibit cytokine secretion by human peripheral blood T cells in vitro through mechanisms independent of the induction of lymphocyte death.
International Immunology, 1996
Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by t... more Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by the severe T lymphopenia observed in IL-7-deficient mice. We recently reported that IL-7 preferentially promotes the in vitro expansion of a discrete MHC class I-dependent lymphocyte subset comprising both CD4+ and CD4-CD8- TCR alpha beta + cells bearing several NK cells markers such NK1.1 and Ly-49. These T cells, designated as NK1+ T cells, have the unique property among thymocytes of producing large amounts of IL-4 upon primary stimulation via the TCR. We have further demonstrated that thymic NK1+ T cells of non-obese diabetic (NOD) mice, a spontaneous model of autoimmune type I diabetes, are markedly deficient in maturation both quantitatively and functionally (IL-4 production). In the present experiments, the addition of exogenous IL-7 completely restored IL-4 production by anti-TCR alpha beta-stimulated mature (HSA-CD8-) thymocytes in NOD mice. A short 2 h preincubation with IL-7 was sufficient to restore both the expression of IL-4 mRNA and IL-4 production capacity. This was related to a direct effect on NK1+ thymocytes since: (i) the effect of IL-7 was restricted to the non-mainstream MEL-14- 3G11- TCR alpha beta + subset which mostly concentrates the IL-4-producing capacity and (ii) IL-7 did not restore IL-4 production in class I-deficient mice which lack the NK1+ T cell subset. Importantly, this activity of IL-7 on NK1+ T cells was also demonstrated in non-autoimmune strains of mice. These results were extended in vivo by showing that the IL-7 treatment significantly increased the anti-CD3 triggered IL-4 production by NK1+ T spleen cells. These findings confirm the role of IL-7 in NK1+ T cell maturation and suggest that the NK1+ T cell defect in NOD mice could be related to insufficient intrathymic IL-7 bioavailability.
Proceedings of The National Academy of Sciences, 1996
Escherichia coli selenophosphate synthetase (SPS, the selD gene product) catalyzes the production... more Escherichia coli selenophosphate synthetase (SPS, the selD gene product) catalyzes the production of monoselenophosphate, the selenium donor compound required for synthesis of selenocysteine (Sec) and seleno-tRNAs. We report the molecular cloning of human and mouse homologs of the selD gene, designated Sps2, which contains an in-frame TGA codon at a site corresponding to the enzyme's putative active site. These sequences allow the identification of selD gene homologs in the genomes of the bacterium Haemophilus influenzae and the archaeon Methanococcus jannaschii, which had been previously misinterpreted due to their in-frame TGA codon. Sps2 mRNA levels are elevated in organs previously implicated in the synthesis of selenoproteins and in active sites of blood cell development. In addition, we show that Sps2 mRNA is up-regulated upon activation of T lymphocytes and have mapped the Sps2 gene to mouse chromosome 7. Using the mouse gene isolated from the hematopoietic cell line FDCPmixA4, we devised a construct for protein expression that results in the insertion of a FLAG tag sequence at the N terminus of the SPS2 protein. This strategy allowed us to document the readthrough of the in-frame TGA codon and the incorporation of 75Se into SPS2. These results suggest the existence of an autoregulatory mechanism involving the incorporation of Sec into SPS2 that might be relevant to blood cell biology. This mechanism is likely to have been present in ancient life forms and conserved in a variety of living organisms from all domains of life.
Immunity, 2006
The nature of dendritic cell(s) (DC[s]) that conditions efficient in vivo priming of CD8 + CTL af... more The nature of dendritic cell(s) (DC[s]) that conditions efficient in vivo priming of CD8 + CTL after immunization via epithelial tissues remains largely unknown. Here, we show that myeloid DCs rapidly recruited by adjuvants into the buccal mucosa or skin are essential for CD8 + T cell crosspriming. Recruitment of circulating DC precursors, including Gr1 + monocytes, precedes the sequential accumulation of CD11c + MHC class II + DCs in dermis and epithelium via a CCR6/ CCL20-dependent mechanism. Remarkably, a defect in CCR6, local neutralization of CCL20, or depletion of monocytes prevents in vivo priming of CD8 + CTL against an innocuous protein antigen administered with adjuvant. In addition, transfer of CCR6-sufficient Gr1 + monocytes restores CD8 + T cell priming in CCR6 º/º mice via a direct Ag presentation mechanism. Thus, newly recruited DCs likely derived from circulating monocytes are responsible for efficient crosspriming of CD8 + CTL after mucosal or skin immunization.
DC function as sentinels of the immune system. They traffic from the blood to the tissues where, ... more DC function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. They then leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. This suggestive link between DC traffic pattern and functions led to the investigation of the chemokine responsiveness of DC during their development and maturation. These studies have shown that immature and mature DC are not recruited by the same chemokines. Immature DC respond to many CC-and CXC-chemokines (MIP-1␣, MIP-1, MIP-5, MCP-3, MCP-4, RANTES, TECK, and SDF-1) and in particular to MIP-3␣/LARC, which acts through CCR6, a receptor mainly expressed in DC and lymphocytes. Like most other chemokines acting on immature DC, MIP-3␣ is inducible on inflammatory stimuli. In contrast, mature DC have lost their responsiveness to most of these chemokines through receptor down-regulation or desensitization, but acquired responsiveness to MIP-3/ELC and 6Ckine/SLC as a consequence of CCR7 up-regulation. MIP-3␣ mRNA is only detected within inflamed epithelial crypts of tonsils, the site of antigen entry known to be infiltrated by immature DC, whereas MIP-3 and 6Ckine are specifically expressed in the T cell-rich areas where mature IDC home. These observations suggest a role for chemokines induced on inflammation such as MIP-3␣ in recruitment of immature DC at the site of injury and a role for MIP-3/6Ckine in accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node. A better understanding of the regulation of DC trafficking might offer new opportunities of therapeutic interventions to suppress or stimulate the immune response. J. Leukoc. Biol. 66: 252-262; 1999.
Springer Seminars in Immunopathology, 2000
DC (dendritic cells) represent an heterogeneous family of cells which function as sentinels of th... more DC (dendritic cells) represent an heterogeneous family of cells which function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. Then, following inflammatory stimuli, they leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. The key role of DC migration in their sentinel function led to the investigation of the chemokine responsiveness of DC populations during their development and maturation. These studies have shown that immature DC respond to many CC and CXC chemokines (MIP-lα, MIP-iβ, MIP-3α, MIP-5, MCP-3, MCP-4, RANTES, TECK and SDF-1) which are inducible upon inflammatory stimuli. Importantly, each immature DC population displays a unique spectrum of chemokine responsiveness. For examples, Langerhans cells migrate selectively to MIP-3α (via CCR6), blood CDllc+ DC to MCP chemokines (via CCR2), monocytes derived-DC respond to MIP-lα/β (via CCR1 and CCR5), while blood CDllc- DC precursors do not respond to any of these chemokines. All these chemokines are inducible upon inflammatory stimuli, in particular MIP-3α, which is only detected within inflamed epithelium, a site of antigen entry known to be infiltrated by immature DC. In contrast to immature DC, mature DC lose their responsiveness to most of these inflammatory chemokines through receptor down-regulation or desensitization, but acquire responsiveness to ELC/MIP-3β and SLCASCkine as a consequence of CCR7 up-regulation. ELC/MIP-3(3 and SLC/6Ckine are specifically expressed in the T-cell-rich areas where mature DC home to become interdigitating DC. Altogether, these observations suggest that the inflammatory chemokines secreted at the site of pathogen invasion will determine the DC subset recruited and will influence the class of the immune response initiated. In contrast, MIP-3β/6Ckine have a determinant role in the accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node, as illustrated by recent observations in mice deficient for CCR7 or SLC/6Ckine. A better understanding of the regulation of DC trafficking might offer new opportunities of therapeutic interventions to suppress, stimulate or deviate the immune response.
DCs (dendritic cells) function as sentinels of the immune system. They traffic from the blood to ... more DCs (dendritic cells) function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they capture antigens. They then leave the tissues and move to the draining lymphoid organs where, converted into mature DC, they prime naive T cells. This suggestive link between DC traffic pattern and functions led us to investigate the chemokine responsiveness of DCs during their development and maturation. DCs were differentiated either from CD34 ϩ hematopoietic progenitor cells (HPCs) cultured with granulocyte/macrophage colony-stimulating factor (GM-CSF) plus tumor necrosis factor (TNF)-␣ or from monocytes cultured with GM-CSF plus interleukin 4. Immature DCs derived from CD34 ϩ HPCs migrate most vigorously in response to macrophage inflammatory protein (MIP)-3 ␣ , but also to MIP-1 ␣ and RANTES (regulated on activation, normal T cell expressed and secreted). Upon maturation, induced by either TNF-␣ , lipopolysaccharide, or CD40L, DCs lose their response to these three chemokines when they acquire a sustained responsiveness to a single other chemokine, MIP-3  . CC chemokine receptor (CCR)6 and CCR7 are the only known receptors for MIP-3 ␣ and MIP-3  , respectively. The observation that CCR6 mRNA expression decreases progressively as DCs mature, whereas CCR7 mRNA expression is sharply upregulated, provides a likely explanation for the changes in chemokine responsiveness. Similarly, MIP-3  responsiveness and CCR7 expression are induced upon maturation of monocytederived DCs. Furthermore, the chemotactic response to MIP-3  is also acquired by CD11c ϩ DCs isolated from blood after spontaneous maturation. Finally, detection by in situ hybridization of MIP-3 ␣ mRNA only within inflamed epithelial crypts of tonsils, and of MIP-3  mRNA specifically in T cell-rich areas, suggests a role for MIP-3 ␣ /CCR6 in recruitment of immature DCs at site of injury and for MIP-3  /CCR7 in accumulation of antigen-loaded mature DCs in T cell-rich areas.
Dendritic cells (DCs) form a network comprising different populations that initiate and different... more Dendritic cells (DCs) form a network comprising different populations that initiate and differentially regulate immune responses. Langerhans cells (LCs) represent a unique population of DCs colonizing epithelium, and we present here observations suggesting that macrophage inflammatory protein (MIP)-3 ␣ plays a central role in LC precursor recruitment into the epithelium during inflammation. (a) Among DC populations, MIP-3 ␣ was the most potent chemokine inducing the selective migration of in vitro-generated CD34 ϩ hematopoietic progenitor cell-derived LC precursors and skin LCs in accordance with the restricted MIP-3 ␣ receptor (CC chemokine receptor 6) expression to these cells. (b) MIP-3 ␣ was mainly produced by epithelial cells, and the migration of LC precursors induced by the supernatant of activated skin keratinocytes was completely blocked with an antibody against MIP-3 ␣ . (c) In vivo, MIP-3 ␣ was selectively produced at sites of inflammation as illustrated in tonsils and lesional psoriatic skin where MIP-3 ␣ upregulation appeared associated with an increase in LC turnover. (d) Finally, the secretion of MIP-3 ␣ was strongly upregulated by cells of epithelial origin after inflammatory stimuli (interleukin 1  plus tumor necrosis factor ␣ ) or T cell signals. Results of this study suggest a major role of MIP-3 ␣ in epithelial colonization by LCs under inflammatory conditions and immune disorders, and might open new ways to control epithelial immunity.
European Journal of Immunology, 2002
To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to trav... more To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to traverse the endothelial barrier, progress through the tissue (i.e. dermis) and cross the dermoepithelial junction (basal membrane). In the present study, we demonstrate that (1) circulating blood DC and monocytes express high levels of CCR2 and primarily respond to monocyte chemotactic protein (MCP) and not to macrophage inflammatory protein (MIP)-3 § / CCL20; (2) while the CD34 + hematopoietic progenitor cells (HPC)-derived CD1a + precursors committed to Langerhans cell differentiation primarily respond to MIP-3 § /CCL20, the HPCderived CD14 + precursors respond to both MCP and MIP-3 § /CCL20; (3) in concordance with the sequential expression of CCR2 and CCR6, the HPC-derived CD14 + precursors initially acquire the ability to migrate in response to MCP-4/CCL13 and subsequently in response to MIP-3 § /CCL20; and (4) in vivo, in inflamed epithelium, MCP-4/CCL13 and MIP-3 § /CCL20 form complementary gradients, with MCP-4/CCL13 expressed in basal epithelial cells at the contact of blood vessels, while MIP-3 § /CCL20 expression is restricted to epithelial cells bordering the external milieu. These observations suggest that the recruitment of DC to the site of infection is controlled by the sequential action of different chemokines: (i) CCR2 + circulating DC or DC precursors are mobilized into the tissue via the expression of MCP by cells lining blood vessels, and (ii) these cells traffic from the tissue to the site of pathogen invasion via the production of MIP-3 § /CL20 by epithelial cells and the up-regulation of CCR6 in response to the tissue environment.
and plasmacytoid DC (pDCs) has been suggested to influence the type of immune response induced by... more and plasmacytoid DC (pDCs) has been suggested to influence the type of immune response induced by microbial pathogens. In this study we show that, in vivo, cDCs and pDCs are equally activated by TLR4, -7, and -9 ligands. Type I interferon (IFN) was important for pDC activation in vivo in response to all three TLR ligands, whereas cDCs required type I IFN signaling only for TLR9-and partially for TLR7-mediated activation. Although TLR ligands induced in situ migration of spleen cDC into the T cell area, spleen pDCs formed clusters in the marginal zone and in the outer T cell area 6 h after injection of TLR9 and TLR7 ligands, respectively. In vivo treatment with TLR9 ligands decreased pDC ability to migrate ex vivo in response to IFN-induced CXCR3 ligands and increased their response to CCR7 ligands. Unlike cDCs, the migration pattern of pDCs required type I IFN for induction of CXCR3 ligands and responsiveness to CCR7 ligands. These data demonstrate that mouse pDCs differ from cDCs in the in vivo response to TLR ligands, in terms of pattern and type I IFN requirement for activation and migration.
Transplantation, 2002
Dendritic cells (DC) are a heterogeneous family of cells that function as sentinels of the immune... more Dendritic cells (DC) are a heterogeneous family of cells that function as sentinels of the immune system. This article summarizes observations suggesting that inflammatory chemokines secreted at the site of pathogen invasion determine the DC subset recruited and influence the class of the immune response initiated. Langerhans cells are selectively recruited by MIP-3alpha/CCL20. In contrast, CCR7 ligands have a key role in the accumulation of antigen-loaded mature DC in T cell-rich areas of the draining lymph node. Improved understanding of the regulation of DC trafficking might offer new opportunities for therapeutic interventions to control immune responses.
European Journal of Immunology, 2002
To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to trav... more To reach the site of antigen deposition at epithelial surfaces, dendritic cells (DC) have to traverse the endothelial barrier, progress through the tissue (i.e. dermis) and cross the dermoepithelial junction (basal membrane). In the present study, we demonstrate that (1) circulating blood DC and monocytes express high levels of CCR2 and primarily respond to monocyte chemotactic protein (MCP) and not to macrophage inflammatory protein (MIP)-3 § / CCL20; (2) while the CD34 + hematopoietic progenitor cells (HPC)-derived CD1a + precursors committed to Langerhans cell differentiation primarily respond to MIP-3 § /CCL20, the HPCderived CD14 + precursors respond to both MCP and MIP-3 § /CCL20; (3) in concordance with the sequential expression of CCR2 and CCR6, the HPC-derived CD14 + precursors initially acquire the ability to migrate in response to MCP-4/CCL13 and subsequently in response to MIP-3 § /CCL20; and (4) in vivo, in inflamed epithelium, MCP-4/CCL13 and MIP-3 § /CCL20 form complementary gradients, with MCP-4/CCL13 expressed in basal epithelial cells at the contact of blood vessels, while MIP-3 § /CCL20 expression is restricted to epithelial cells bordering the external milieu. These observations suggest that the recruitment of DC to the site of infection is controlled by the sequential action of different chemokines: (i) CCR2 + circulating DC or DC precursors are mobilized into the tissue via the expression of MCP by cells lining blood vessels, and (ii) these cells traffic from the tissue to the site of pathogen invasion via the production of MIP-3 § /CL20 by epithelial cells and the up-regulation of CCR6 in response to the tissue environment.
Nature Immunology, 2001
We show here that mouse interferon-alpha (IFN-alpha)-producing cells (mIPCs) are a unique subset ... more We show here that mouse interferon-alpha (IFN-alpha)-producing cells (mIPCs) are a unique subset of immature antigen-presenting cells (APCs) that secrete IFN-alpha upon stimulation with viruses. mIPCs have a plasmacytoid morphology, can be stained with an antibody to Ly6G and Ly6C (anti-Ly6G/C) and are Ly6C+B220+CD11cloCD4+; unlike other dendritic cell subsets, however, they do not express CD8alpha or CD11b. Although mIPCs undergo apoptosis in vitro, stimulation with viruses, IFN-alpha or CpG oligonucleotides enhanced their survival and T cell stimulatory activity. In vivo, mIPCs were the main producers of IFN-alpha in cytomegalovirus-infected mice, as depletion of Ly6G+/C+ cells abrogated IFN-alpha production. mIPCs produced interleukin 12 (IL-12) in response to viruses and CpG oligodeoxynucleotides, but not bacterial products. Although different pathogens can selectively engage various APC subsets for IL-12 production, IFN-alpha production is restricted to mIPCs' response to viral infection.
Immunological Reviews, 2008
Summary: Interleukin-10 (IL-10) is a cytokine with broad anti-inflammatory properties by its supp... more Summary: Interleukin-10 (IL-10) is a cytokine with broad anti-inflammatory properties by its suppression of both macrophage and dendritic cell function, including antigen-presenting cell function and the production of proinflammatory cytokines. This can result subsequently in the feedback regulation of both T-helper 1 (Th1)-type and Th2-type responses. This review discusses the potential use of IL-10 or agents that induce IL-10 as potential anti-inflammatory therapies in inflammatory diseases. Although IL-10-deficient mice develop colitis in the presence of normal gut flora and clear certain intracellular pathogens more efficiently, this is often accompanied by immunopathology, which can be lethal to the host. This reinforces the anti-inflammatory properties of IL-10, although it should be noted that as discussed below, IL-10 can also promote B-cell and other immune responses under particular settings. A penalty of its role to limit the immune and inflammatory responses to pathogens and prevent damage to the host is that high or dysregulated levels of IL-10 may result in chronic infection. Thus, antagonists of IL-10 show great potential as adjuvants in preventative or therapeutic vaccines against chronic infection or cancer. This article reviews basic published studies on IL-10, which may lead to potential uses of IL-10 or its antagonists in human disease.
Cladribine (2-chloro-2&am... more Cladribine (2-chloro-2'-deoxyadenosine) is a purine nucleoside analogue (PNA) which causes targeted and sustained reduction of peripheral lymphocyte counts. Cladribine tablets produced significant treatment benefit for patients with relapsing-remitting multiple sclerosis in the phase 3 CLARITY study. In addition to the well-characterised cell-specific phosphorylation of PNAs responsible for lymphocyte reduction, the mode of action of cladribine may encompass distinct activities contributing to its overall effects on the immune system. Here we demonstrate that clinically relevant concentrations of cladribine also inhibit cytokine secretion by human peripheral blood T cells in vitro through mechanisms independent of the induction of lymphocyte death.