The Experts below are selected from a list of 18000 Experts worldwide ranked by ideXlab platform
Dan R Littman - One of the best experts on this subject based on the ideXlab platform.
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the differentiation of human th 17 cells requires transforming growth factor β and induction of the nuclear Receptor rorγt
Nature Immunology, 2008Co-Authors: Nicolas Manel, Derya Unutmaz, Dan R LittmanAbstract:T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear Receptor RORgammat. It has been suggested that the differentiation of human T(H)-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF-beta upregulated RORgammat expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORgammat-directed IL-17 expression. Other gene products detected in T(H)-17 cells after RORgammat induction included the Chemokine Receptor CCR6, the IL-23 Receptor, IL-17F and IL-26. Our studies identify RORgammat as having a central function in the differentiation of human T(H)-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
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the differentiation of human t h 17 cells requires transforming growth factor beta and induction of the nuclear Receptor rorgammat
Nature Immunology, 2008Co-Authors: Nicolas Manel, Derya Unutmaz, Dan R LittmanAbstract:T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear Receptor RORgammat. It has been suggested that the differentiation of human T(H)-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF-beta upregulated RORgammat expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORgammat-directed IL-17 expression. Other gene products detected in T(H)-17 cells after RORgammat induction included the Chemokine Receptor CCR6, the IL-23 Receptor, IL-17F and IL-26. Our studies identify RORgammat as having a central function in the differentiation of human T(H)-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
Nicolas Manel - One of the best experts on this subject based on the ideXlab platform.
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the differentiation of human th 17 cells requires transforming growth factor β and induction of the nuclear Receptor rorγt
Nature Immunology, 2008Co-Authors: Nicolas Manel, Derya Unutmaz, Dan R LittmanAbstract:T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear Receptor RORgammat. It has been suggested that the differentiation of human T(H)-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF-beta upregulated RORgammat expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORgammat-directed IL-17 expression. Other gene products detected in T(H)-17 cells after RORgammat induction included the Chemokine Receptor CCR6, the IL-23 Receptor, IL-17F and IL-26. Our studies identify RORgammat as having a central function in the differentiation of human T(H)-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
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the differentiation of human t h 17 cells requires transforming growth factor beta and induction of the nuclear Receptor rorgammat
Nature Immunology, 2008Co-Authors: Nicolas Manel, Derya Unutmaz, Dan R LittmanAbstract:T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear Receptor RORgammat. It has been suggested that the differentiation of human T(H)-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF-beta upregulated RORgammat expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORgammat-directed IL-17 expression. Other gene products detected in T(H)-17 cells after RORgammat induction included the Chemokine Receptor CCR6, the IL-23 Receptor, IL-17F and IL-26. Our studies identify RORgammat as having a central function in the differentiation of human T(H)-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
Joost J Oppenheim - One of the best experts on this subject based on the ideXlab platform.
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human beta defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with ccr2
Journal of Immunology, 2010Co-Authors: Johann Rohrl, De Yang, Joost J Oppenheim, Thomas HehlgansAbstract:Beta-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain beta-defensin family members to chemoattract immature dendritic cells and CD45RO+ CD4+ T cells through Chemokine Receptor CCR6. However, because beta-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other Receptors for these polypeptides. In this study, we demonstrate the capacity of human beta-defensin (hBD)2 and 3 and their mouse orthologs, beta-defensin 4 and 14, to interact with CCR2, a Chemokine Receptor expressed on monocytes, macrophages, and neutrophils. These beta-defensins, fused to the Fc region of human IgG1, showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The beta-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the Chemokine ligand for CCR2, abolished migration induced by beta-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the beta-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (beta-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
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human β defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with ccr2
Journal of Immunology, 2010Co-Authors: Johann Rohrl, De Yang, Joost J Oppenheim, Thomas HehlgansAbstract:β-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain β-defensin family members to chemoattract immature dendritic cells and CD45RO + CD4 + T cells through Chemokine Receptor CCR6. However, because β-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other Receptors for these polypeptides. In this study, we demonstrate the capacity of human β-defensin (hBD)2 and 3 and their mouse orthologs, β-defensin 4 and 14, to interact with CCR2, a Chemokine Receptor expressed on monocytes, macrophages, and neutrophils. These β-defensins, fused to the Fc region of human IgG 1 , showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The β-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the Chemokine ligand for CCR2, abolished migration induced by β-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the β-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (β-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
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many Chemokines including ccl20 mip 3α display antimicrobial activity
Journal of Leukocyte Biology, 2003Co-Authors: De Yang, Qian Chen, David M Hoover, Patricia Staley, Kenneth Tucker, Jacek Lubkowski, Joost J OppenheimAbstract:Previous studies have demonstrated that -defensins exhibit chemotactic activity by sharing the Chemokine Receptor CCR6 with the CC Chemokine ligand CCL20/macrophage-inflamma- tory protein-3 (MIP-3). Structural analysis of CCL20/MIP-3 revealed that most of the positively charged residues are concentrated at one area of its topological surface, a characteristic considered to be important for the antimicrobial activity of defensins. Here, we report that similar to de- fensins, CCL20/MIP-3 has antimicrobial effects on Escherichia coli, Pseudomonas aeruginosa, Moraxella catarrhalis, Streptococcus pyogenes, Enterococcus faecium, Staphylococcus aureus, and Candida albicans. Additionally, by screening a total of 30 human Chemokines, we have identified an additional 17 human Chemokines, which exhibit antimicrobial activity in vitro. Collectively, about two-thirds of the Chemokines investigated so far has the capacity to kill microorganisms in vitro, suggesting that antimicrobial activity may be an- other host-defense function for certain chemo- kines. Comparison of the structural characteristics between antimicrobial and nonantimicrobial che- mokines suggests that topological formation of a large, positively charged electrostatic patch on the surface of the molecule is likely to be a common structural feature of antimicrobial Chemokines. J. Leukoc. Biol. 74: 448-455; 2003.
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engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human β defensin 3
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: David M Hoover, De Yang, Joost J Oppenheim, Cyril Boulegue, Fanny Santamaria, Jacek LubkowskiAbstract:Abstract Human defensins form a family of small, cationic, and Cys-rich antimicrobial proteins that play important roles in innate immunity against invading microbes. They also function as effective immune modulators in adaptive immunity by selectively chemoattracting T lymphocytes and immature dendritic cells. On the basis of sequence homology and the connectivity of six conserved Cys residues, human defensins are classified into α and β families. Structures of several β-defensins have recently been characterized, confirming the disulfide connectivity conserved within the family, i.e., Cys1–Cys5, Cys2–Cys4, and Cys3–Cys6. We found that human β-defensin 3 (hBD3), a recently described member of the growing β family, did not fold preferentially into a native conformation in vitro under various oxidative conditions. Using the orthogonal protection of Cys1–Cys5 and of Cys1–Cys6, we chemically synthesized six topological analogs of hBD3 with predefined disulfide connectivities, including the (presumably) native β pairing. Unexpectedly, all differently folded hBD3 species exhibited similar antimicrobial activity against Escherichia coli, whereas a wide range of chemotactic activities was observed with these analogs for monocytes and cells transfected by the Chemokine Receptor CCR6. Furthermore, whereas substitution of all Cys residues by α-aminobutyric acid completely abolished the chemotactic activity of hBD3, the bactericidal activity remained unaffected in the absence of any disulfide bridge. Our findings demonstrate that disulfide bonding in hBD3, although required for binding and activation of Receptors for chemotaxis, is fully dispensable for its antimicrobial function, thus shedding light on the mechanisms of action for human β-defensins and the design of novel peptide antibiotics.
De Yang - One of the best experts on this subject based on the ideXlab platform.
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human beta defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with ccr2
Journal of Immunology, 2010Co-Authors: Johann Rohrl, De Yang, Joost J Oppenheim, Thomas HehlgansAbstract:Beta-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain beta-defensin family members to chemoattract immature dendritic cells and CD45RO+ CD4+ T cells through Chemokine Receptor CCR6. However, because beta-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other Receptors for these polypeptides. In this study, we demonstrate the capacity of human beta-defensin (hBD)2 and 3 and their mouse orthologs, beta-defensin 4 and 14, to interact with CCR2, a Chemokine Receptor expressed on monocytes, macrophages, and neutrophils. These beta-defensins, fused to the Fc region of human IgG1, showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The beta-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the Chemokine ligand for CCR2, abolished migration induced by beta-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the beta-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (beta-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
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human β defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with ccr2
Journal of Immunology, 2010Co-Authors: Johann Rohrl, De Yang, Joost J Oppenheim, Thomas HehlgansAbstract:β-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain β-defensin family members to chemoattract immature dendritic cells and CD45RO + CD4 + T cells through Chemokine Receptor CCR6. However, because β-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other Receptors for these polypeptides. In this study, we demonstrate the capacity of human β-defensin (hBD)2 and 3 and their mouse orthologs, β-defensin 4 and 14, to interact with CCR2, a Chemokine Receptor expressed on monocytes, macrophages, and neutrophils. These β-defensins, fused to the Fc region of human IgG 1 , showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The β-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the Chemokine ligand for CCR2, abolished migration induced by β-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the β-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (β-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
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many Chemokines including ccl20 mip 3α display antimicrobial activity
Journal of Leukocyte Biology, 2003Co-Authors: De Yang, Qian Chen, David M Hoover, Patricia Staley, Kenneth Tucker, Jacek Lubkowski, Joost J OppenheimAbstract:Previous studies have demonstrated that -defensins exhibit chemotactic activity by sharing the Chemokine Receptor CCR6 with the CC Chemokine ligand CCL20/macrophage-inflamma- tory protein-3 (MIP-3). Structural analysis of CCL20/MIP-3 revealed that most of the positively charged residues are concentrated at one area of its topological surface, a characteristic considered to be important for the antimicrobial activity of defensins. Here, we report that similar to de- fensins, CCL20/MIP-3 has antimicrobial effects on Escherichia coli, Pseudomonas aeruginosa, Moraxella catarrhalis, Streptococcus pyogenes, Enterococcus faecium, Staphylococcus aureus, and Candida albicans. Additionally, by screening a total of 30 human Chemokines, we have identified an additional 17 human Chemokines, which exhibit antimicrobial activity in vitro. Collectively, about two-thirds of the Chemokines investigated so far has the capacity to kill microorganisms in vitro, suggesting that antimicrobial activity may be an- other host-defense function for certain chemo- kines. Comparison of the structural characteristics between antimicrobial and nonantimicrobial che- mokines suggests that topological formation of a large, positively charged electrostatic patch on the surface of the molecule is likely to be a common structural feature of antimicrobial Chemokines. J. Leukoc. Biol. 74: 448-455; 2003.
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engineering disulfide bridges to dissect antimicrobial and chemotactic activities of human β defensin 3
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: David M Hoover, De Yang, Joost J Oppenheim, Cyril Boulegue, Fanny Santamaria, Jacek LubkowskiAbstract:Abstract Human defensins form a family of small, cationic, and Cys-rich antimicrobial proteins that play important roles in innate immunity against invading microbes. They also function as effective immune modulators in adaptive immunity by selectively chemoattracting T lymphocytes and immature dendritic cells. On the basis of sequence homology and the connectivity of six conserved Cys residues, human defensins are classified into α and β families. Structures of several β-defensins have recently been characterized, confirming the disulfide connectivity conserved within the family, i.e., Cys1–Cys5, Cys2–Cys4, and Cys3–Cys6. We found that human β-defensin 3 (hBD3), a recently described member of the growing β family, did not fold preferentially into a native conformation in vitro under various oxidative conditions. Using the orthogonal protection of Cys1–Cys5 and of Cys1–Cys6, we chemically synthesized six topological analogs of hBD3 with predefined disulfide connectivities, including the (presumably) native β pairing. Unexpectedly, all differently folded hBD3 species exhibited similar antimicrobial activity against Escherichia coli, whereas a wide range of chemotactic activities was observed with these analogs for monocytes and cells transfected by the Chemokine Receptor CCR6. Furthermore, whereas substitution of all Cys residues by α-aminobutyric acid completely abolished the chemotactic activity of hBD3, the bactericidal activity remained unaffected in the absence of any disulfide bridge. Our findings demonstrate that disulfide bonding in hBD3, although required for binding and activation of Receptors for chemotaxis, is fully dispensable for its antimicrobial function, thus shedding light on the mechanisms of action for human β-defensins and the design of novel peptide antibiotics.
Thomas Hehlgans - One of the best experts on this subject based on the ideXlab platform.
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human beta defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with ccr2
Journal of Immunology, 2010Co-Authors: Johann Rohrl, De Yang, Joost J Oppenheim, Thomas HehlgansAbstract:Beta-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain beta-defensin family members to chemoattract immature dendritic cells and CD45RO+ CD4+ T cells through Chemokine Receptor CCR6. However, because beta-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other Receptors for these polypeptides. In this study, we demonstrate the capacity of human beta-defensin (hBD)2 and 3 and their mouse orthologs, beta-defensin 4 and 14, to interact with CCR2, a Chemokine Receptor expressed on monocytes, macrophages, and neutrophils. These beta-defensins, fused to the Fc region of human IgG1, showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The beta-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the Chemokine ligand for CCR2, abolished migration induced by beta-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the beta-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (beta-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
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human β defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with ccr2
Journal of Immunology, 2010Co-Authors: Johann Rohrl, De Yang, Joost J Oppenheim, Thomas HehlgansAbstract:β-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain β-defensin family members to chemoattract immature dendritic cells and CD45RO + CD4 + T cells through Chemokine Receptor CCR6. However, because β-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other Receptors for these polypeptides. In this study, we demonstrate the capacity of human β-defensin (hBD)2 and 3 and their mouse orthologs, β-defensin 4 and 14, to interact with CCR2, a Chemokine Receptor expressed on monocytes, macrophages, and neutrophils. These β-defensins, fused to the Fc region of human IgG 1 , showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The β-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the Chemokine ligand for CCR2, abolished migration induced by β-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the β-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (β-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.