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(Journal of Leukocyte Biology. 2000;68:9-14.)
© 2000 by Society for Leukocyte Biology

Human neutrophil defensins selectively chemoattract naive T and immature dendritic cells

De Yang^*, Qian Chen^*, Oleg Chertov and Joost J. Oppenheim^*

^* Laboratory of Molecular Immunoregulation, Division of Basic Sciences,
Intramural Research Support Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland

Correspondence: Dr. Joost J. Oppenheim, LMI, DBS, NCI-FCRDC, Building 560, Room 21-89, Frederick, MD 21702-1201. E-mail: oppenhei{at}mail.ncifcrf.gov

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Defensins, a family of cationic, structurally related, antimicrobial peptides, contribute to host defense by disrupting the cytoplasmic membrane of microbes. Here we show that human neutrophil defensins selectively induce the migration of human CD4⁺/CD45RA⁺ naive and CD8⁺, but not CD4⁺/CD45RO⁺ memory, T cells. Moreover, human neutrophil defensins are chemotactic for immature human dendritic cells derived from either CD34⁺ progenitors or peripheral blood monocytes. Upon maturation induced by treatment with tumor necrosis factor (TNF-), dendritic cells lose their responsiveness to human neutrophil defensins. The chemotactic effect of human neutrophil defensins on both T and dendritic cells is pertussis toxin-sensitive, suggesting that a G_i protein-coupled receptor is responsible. Human neutrophil defensins are also chemotactic for immature murine dendritic cells. These data suggest that, in addition to their antimicrobial role, human neutrophil defensins also contribute to adaptive immunity by mobilizing T cells and dendritic cells.

Key Words: -defensins • chemotaxis • T lymphocytes

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Defensins, comprising a family of small (3.5–4.5 kDa) cationic antimicrobial peptides with three to four intramolecular cysteine disulfide bonds, are widely distributed in mammals, insects, and plants [^{1 2 3 4} ]. Based on the pattern of their cysteine residues and disulfide connections, defensins in vertebrates are divided into two categories, designated as and ß [² , ³ ]. In humans, six and two ß defensins have thus far been characterized [² , ³ , ⁵ , ⁶ ]. Human defensins 5 and 6 are generated by small intestine Paneth cells [³ ], whereas defensins 1, 2, 3, and 4 are expressed by neutrophils and thus are termed human neutrophil peptide (HNP) [¹ , ⁷ ]. All defensins are considered to contribute to host defense because they preferentially disrupt the cell membranes of microorganisms that are rich in negatively charged phospholipids [^{1 2 3} , ^{5 6 7 8} ].

In addition to their antimicrobial effects, defensins have also been reported to lyse some tumor cells [⁹ ], to chemoattract monocytes [¹⁰ ], to block the adrenocorticotropin receptor [¹¹ ], to inhibit NADPH oxidase activation [¹² ], to be mitogenic for murine epithelial cells and fibroblasts [¹³ ], to initiate [¹⁴ ] or suppress [¹⁵ ] the classical pathway of complement, and to promote the binding of lipoproteins to vascular matrix [¹⁶ ]. By analyzing interleukin-8 (IL-8)-induced neutrophil-derived T cell attracting activity, our laboratory previously established that HNP is chemotactic for human T cells [¹⁷ ]. Work from our and other’s laboratories also demonstrates that, when administered in vivo together with antigens, HNP is capable of promoting systemic antigen-specific immune responses [18, and K. Tani et al., unpublished results]. However, the mechanisms by which HNP enhances adaptive immunity remain largely unclear.

Quite recently, we documented that human ß defensins induce the migration of both human resting memory T cells and immature dendritic cells (DC) by interacting with CC chemokine receptor 6 and proposed that ß defensins may bridge innate and adaptive immunity of the host [²⁰ ]. Because lymphocytes and DC are participants in adaptive immunity [²¹ ], we therefore investigated the mechanism by which HNP enhances adaptive immunity by determining: (1) the identity of the subsets of human T cells chemoattracted by HNP, and (2) whether or not HNP was also chemotactic for DCs. The results suggest that HNP selectively targets distinct subsets of T cells and DCs.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Reagents
All cytokines used were recombinant proteins. Regulated on activation and normal T cell expressed (RANTES), tumor necrosis factor (TNF-; specific activity 2 x 10⁷ U/mg), granulocyte-macrophage colony-stimulating factor (GM-CSF; specific activity 10⁷ U/mg), IL-4 (specific activity 2 x 10⁶ U/mg), and recombinant HNP1 (rHNP1) were purchased from PeproTech (Rocky Hill, NJ). N-formyl-Met-Leu-Phe (fMLP), synthetic HNP2 (sHNP2), and chemicals, unless otherwise specified, were purchased from Sigma (St. Louis, MO). sHNP1 was obtained from Phoenix (Mountain View, CA). Natural human neutrophil defensins, a mixture of HNP1, 2, and 3 (designated thereafter as HNPm), were isolated from the granules of polymorphonuclear leukocytes from normal donors as described [¹⁷ ]. Amino acid sequence analysis revealed that the proportion of HNP1/HNP2/HNP3 was 5:3:2 in HNPm. No protein contaminants were detected in HNPm by amino acid analysis, matrix-assisted laser desorption ionization, and time-of-flight mass spectrometry.

Cell isolation and purification
Human peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Paque density gradient centrifugation. Monocytes were purified (>95%) from human PBMC with a MACS CD14 monocyte isolation kit (Miltenyi Biotech, Auburn, CA). Human peripheral blood CD3⁺, CD4⁺, CD8⁺, CD4⁺/CD45RA⁺, and CD4⁺/CD45RO⁺ T cells were purified from PBMC by the use of corresponding negative selection columns (R & D Systems, Minneapolis, MN) following the manufacturer’s recommendation. The purity of T cell subset populations was checked by FACScan analysis. Cell populations with purity less than 95% were discarded. Murine Sca-1⁺/Lineage^- hematopoietic stem cells (HSCs) were isolated from the bone marrow of mice (C57BL/6, female, 5- to 7-week-old) by the use of a Sca-1 MultiSort Kit (Miltenyi Biotech). Human cord blood CD34⁺ progenitors (>90%) and CD3⁺ T cells (>95%) were purchased from Poietics (Gaithersburg, MD).

Preparation of DC
Monocyte-derived DCs were generated as described previously [²² ]. In brief, purified monocytes were incubated in the presence of GM-CSF, IL-4, and transforming growth factor ß1 (TGF-ß1) for 7 days to generate immature DCs (iDCs). Mature DCs (mDCs) were obtained by incubating iDCs in the same cytokine-containing medium plus 50 ng/mL of TNF- for 2 days. CD34⁺-derived iDCs and mDCs were prepared from cord blood CD34⁺ progenitors exactly as described elsewhere [²⁰ ]. To generate murine iDCs, purified murine HSCs were incubated in RPMI 1640 (Biowhittaker, Walkersville, MD) containing 10% FBS, glutamine (2 mM), HEPES (25 mM), penicillin (100 U/mL), streptomycin (100 µg/mL), GM-CSF (50 ng/mL), and IL-4 (10 ng/mL) at 37°C in a CO₂ (5%) incubator for 5 days. The cultures were fed with the same cytokine-containing medium every 2–3 days. Murine mDCs were obtained by culture of the iDCs in the same cytokine cocktail plus 50 ng/mL of TNF- for 2 additional days. All the iDCs used were CD86^-/+, MHC class II⁺⁺, and unable to stimulate allogeneic mixed lymphocyte reaction, whereas all mDCs used were CD86⁺⁺, MHC class II⁺⁺⁺⁺, and highly capable of mounting marked allogeneic mixed lymphocyte reaction.

Chemotaxis assay
Cell migration was assessed using a 48-well microchemotaxis chamber. The cells were washed three times and resuspended in chemotactic medium (CM, RPMI1640 containing 1% BSA). HNP and other chemotactic factors were diluted with CM. Different concentrations of chemotactic factors were placed in wells of the lower compartment of the chamber (Neuro Probe, Cabin John, MD), and cell suspension (15 x 10⁶ cells/mL) was added in wells of the upper compartment. The lower and upper compartments were separated by a 5-µm polycarbonate filter (Osmonics, Livermore, CA). For T cell chemotaxis, the filter was coated overnight at 4°C in RPMI 1640 containing 10 µg/mL of fibronectin (Sigma) and air-dried just before use. After incubation at 37°C for 1.5 (for DCs) or 3 h (for T cells) in humidified air with 5% CO₂, the filters were removed, stained, and the cells migrated across the filter were counted with the use of a Bioquant semiautomatic counting system. The results are presented as either the number of cells per high-power field (No./HPF) or chemotactic index (CI) defined as the fold increase in the number of migrating cells in the presence of test factors over the spontaneous cell migration (in the absence of test factors). The statistical significance of the increase in cell migration and difference of cell migration induced by different chemotactic factors was determined by paired and unpaired t test, respectively. A CI 2 is statistically significant (P < 0.05).

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Chemoattraction of peripheral blood CD3⁺ T (PBT) cells by HNP
We initially confirmed the capacity of HNP purified from neutrophils to induce PBT cell migration. As shown by Figure 1 , HNPm chemoattracted PBT cells in a bell-shaped dose-dependent manner with a peak response observed at 10 ng/mL, which is consistent with the previous report [¹⁷ ]. To confirm that HNP in the HNPm preparation was the responsible moiety, we examined preparations of rHNP1 and sHNP1. Both rHNP1 and sHNP1 chemoattracted PBT cells similarly to HNPm (Fig. 1) , suggesting that HNP in HNPm preparation was responsible for the T cell chemotactic effect.

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Figure 1. Migration of human peripheral blood CD3+ T cells in response to HNP. T cell migration was assessed by chemotaxis assay as described in Materials and Methods. CD3+ T cells were used at a concentration of 5 x 106 cells/mL. Spontaneous cell migration (without HNP) was 6090 cells/HPF. Means ± SD of triplicate wells are shown. Similar results were obtained from more than five separate experiments.

Cord blood CD3⁺ T (CBT) cells respond more vigorously to HNP than PBT cells
HNPm and sHNP1 induced the migration of human CBT in a dose-dependent manner with a peak response at 10 ng/mL (Table 1 ). A comparison of HNP-induced migration of CBT and PBT cells revealed that, at identical concentrations, HNPm and sHNP1 chemoattracted more CBT than PBT cells, especially at concentrations ranging from 1 to 10 ng/mL (Table 1) . This difference might be due to (1) greater expression of receptors for HNP by CBT cells, and (2) higher proportion of HNP-responding T cells in CBT cell population. Because it is well-documented that CBT cells contain more naive T cells than PBT cells [²³ , ²⁴ ], we investigated the possibility that naive T cells selectively respond to HNP.

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Table 1. Chemotaxis of CBT and PBT Cells in Response to HNP

Selective chemoattraction by HNP of CD4⁺/CD45RA⁺ and CD8⁺ PBT cells
We first separated CD3⁺ PBT cells into CD4⁺ and CD8⁺ subsets and investigated their responsiveness to HNPm. HNPm induced similar levels of migration of both CD4⁺ and CD8⁺ subsets (Fig. 2A ). When CD4⁺ PBT cells were further separated into CD45RA⁺ and CD45RO⁺ subsets and tested, only CD4⁺/CD45RA⁺ (naive), but not CD4⁺/CD45RO⁺ (memory), T cells responded chemotactically to both HNPm and rHNP1 (Fig. 2B) . A comparison of HNPm-induced migration of CD4⁺/CD45RA⁺ T cells (Fig. 2B , open circle) with that of CD4⁺ T cells (Fig. 2A , filled bar) revealed that naive CD4 cells responded more potently than unfractionated CD4 cells, suggesting that the difference between HNP-induced CBT and PBT cell migration (Table 1) was most likely due to the fact that CBT comprises more naive T cells than PBT [²³ , ²⁴ ].

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Figure 2. Migration of different subsets of human peripheral blood T cells in response to HNP. T cell migration was assessed by chemotaxis assay as described in Materials and Methods. The results are presented as the means ± SD of triplicate wells. (A) Chemotaxis of CD4+ and CD8+ T cells by HNPm. CD4+ and CD8+ T cells were used at a concentration of 2 x 106 cells/mL. Spontaneous cell migration (without HNP) was 5070 cells/HPF. (B) Chemotaxis of naive (CD45RA+) and memory (CD45RO+) CD4+ T cells by HNPm and rHNP1. Naive and memory CD4+ T cells were used at a concentration of 1 x 106 cells/mL. Spontaneous cell migration (without HNP) was 3040 cells/HPF. Similar results were obtained from three separate experiments.

HNP induction of human DC migration
To gain a greater understanding as to how HNP promotes in vivo antigen-specific immune responses [18, K. Tani et al. unpublished results], we studied whether HNP were chemotactic for DC. As shown by Figure 3A , HNPm (filled circles) and sHNP2 (filled triangles) induced the migration of monocyte-derived iDCs in a bell-shaped dose-dependent manner. Monocytes (open triangles) did not respond to HNPm. After maturation by TNF-, mDCs lost the responsiveness to HNPm (Fig. 3A , open circles). Because human DCs can be generated in vitro not only from monocytes [²² , ²⁵ , ²⁶ ], but also from CD34⁺ progenitors [²⁰ , ²⁷ ], we also examined the effect of HNP on CD34⁺ progenitor-derived DCs. Both HNPm and rHNP1 induced the migration of CD34⁺ progenitor-derived iDCs (Fig. 3B) , but not mDCs (data not shown). The effective concentrations of HNP for inducing human iDC migration (Fig. 3) were similar to those for inducing T cell migration (Figs. 1 and 2 , Table 1 ).

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Figure 3. Induction of human DC migration by HNP. Cell migration was assessed by chemotaxis assay as described in Materials and Methods. Monocytes and DCs were used at a concentration of 1 x 106 cells/mL. Means ± SD of triplicate wells are shown. Spontaneous cell migration (without HNP) was 4060 cells/HPF. (A) Migration of monocytes and monocyte-derived DCs in response to HNPm and sHNP2. Monocytes and DCs were from the same donor. The error bars were omitted for clarity. (B) Chemotaxis of CD34+ progenitor-derived iDCs by HNPm and sHNP1. *P < 0.05. One experiment representative of three is shown.

Inhibition of HNPm-induced migration of T and dendritic cells by pertussis toxin (PTX)
Because ligand-induced chemotaxis of leukocytes is often mediated through G protein-coupled seven-transmembrane domain receptors [²⁸ , ²⁹ ], we investigated whether HNP-induced T and DC migration was also mediated by such receptors. Preincubation of PBT cells and monocyte-derived iDC with 100 ng/mL of PTX for 30 min at 37°C completely blocked HNPm-induced migration of PBT cells and iDC (Table 2 ), suggesting that the chemotactic effect of HNP on T and dendritic cells was mediated through a G_i protein-coupled receptor(s). PTX pretreatment did not affect spontaneous (in response to CM) cell migration, ruling out the possibility of nonspecific inhibition of cell motility. That cell migration induced by RANTES or fMLP was also inhibited is compatible with the fact that both RANTES and fMLP use PTX-sensitive G protein-coupled receptors [²⁸ , ²⁹ ].

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Table 2. Inhibition by PTX of HNP-Induced Chemotaxis of Human CD3+ T and Immature Dendritic Cells

HNP selectively chemoattract murine iDCs
Because HNP is effective in mice [¹⁸ , 19], we further investigated the effect of HNP on murine DCs. As shown by Figure 4 , HNPm and sHNP1 induced the migration of murine iDCs with a peak response at 10 ng/mL (open symbols). After TNF--induced maturation, murine mDCs also lost their responsiveness to HNPm and sHNP1 (Fig. 4 , filled symbols).

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Figure 4. Selective chemoattraction of murine iDCs by HNPm and sHNP1. Murine DCs were used at a concentration of 1 x 106 cells/mL in the chemotaxis assay. The results are shown as means ± SD of triplicate wells. Spontaneous cell migration (without HNP) was 3040 cells/HPF. One experiment representative of three is shown.

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this study, we demonstrated that HNP either purified from neutrophil granules or generated by synthetic or recombinant technologies was chemotactic for human peripheral blood T cells (Fig. 1) , confirming our previous report [¹⁷ ]. Based on the observation that HNP was more chemotactic for human cord blood CD3⁺ T cells than human peripheral blood CD3⁺ T cells (Table 1) , we speculated that HNP might act on particular subsets of T cells. Indeed, HNP selectively induced the migration of CD4⁺/CD45RA⁺ naive, but not CD4⁺/CD45RO⁺ memory, T cells. HNP was also chemotactic for human CD8⁺ T cells. Theoretically, CD8⁺ T cells also comprise naive and memory subsets [³⁰ ]. However, unlike CD4⁺ T cells, which can easily be separated into naive and memory subsets based on the expression of either CD45RA or CD45RO [³¹ ], naive and memory CD8 T cells cannot be separated based on the expression of CD45 isoforms [^{32 33 34} ]. Consequently, whether HNP is targeting one subset or both naive and memory CD8⁺ T cells awaits further investigation. Nevertheless, identification of CD8⁺ and CD4⁺/CD45RA⁺ T cells as targets of HNP enriches our understanding of the biological roles of human neutrophil defensins.

DCs are the most potent antigen-presenting cells and are essential for the initial induction of antigen-specific adaptive immunity [²¹ , ³⁵ ]. Establishing the capacity of HNP to chemoattract immature human and murine DCs is of particular interest. This is in accordance with reports that human defensins, when administered together with antigens into mice, promote systemic antigen-specific immune responses in vivo [18, K. Tani et al., unpublished results]. Furthermore, this enables us to propose that, in addition to their microbicidal role [¹ , ² , ⁷ , ⁸ ], human neutrophil defensins also play important roles in promoting adaptive immunity against microorganisms presumably by recruiting immature DCs and T cells to the sites of microbial infection. Neutrophil defensins may participate in several in vivo phases of innate and adaptive immunity against microbial infection: (1) after entry of microorganisms into the host, phagocytic neutrophils migrate to sites of entry and phagocytize microbes; (2) defensins are released by degranulating neutrophils into the local environment [¹⁷ , ³⁶ ] to lyse the microorganisms and to form a chemotactic gradient that induces the migration of iDCs toward the inflammatory sites; (3) iDCs accumulating at the inflammatory sites phagocytize and process microbial antigens, differentiate into mDCs, and display the processed antigenic epitopes on their surfaces in the context of MHC molecules [²¹ , ³⁵ ]; (4) mDCs down-regulate receptors for defensins and other chemotactic ligands [²² , ^{37 38 39} ], and up-regulate CCR7 [^{39 40 41} ], which enables them to migrate away from the inflammatory sites toward the secondary lymphoid tissues where they present antigenic epitopes to lymphocytes to initiate antigen-specific adaptive immune responses [²¹ , ³⁵ ]; (5) local defensin gradient may also facilitate the recruitment of T cells to the inflammatory sites to react to the microorganisms; and (6) defensins may also help fine-tune host immune reactions against invading microorganisms by regulating the activation of the classical complement pathway [¹⁴ , ¹⁵ ]. Apparently, the greater the number of iDCs recruited into inflammatory sites, the greater the antigen-specific antimicrobial immune responses.

Analysis of the dose responses of diverse effects of defensins reveals that two different effective dose ranges exist. High concentrations of defensins (micromolar range) are required to disrupt the cell membranes of microorganisms or some tumor cells [¹ , ² , ^{7 8 9} ], to inhibit NADPH activation [¹² , ⁴² ], to interact with complement C1 [¹⁴ , ¹⁵ ], and to promote the binding of lipoproteins to vascular matrix [¹⁶ ]. In contrast, only low concentrations of defensins (nanomolar range) are sufficient for their mitogenic [¹³ ], corticostatic [¹¹ ], and chemotactic activities [¹⁰ , ¹⁷ ]. High doses of defensins act by forming pore-like structures within the cell membrane or interacting with negatively charged molecules, whereas the low-dose effects may be mediated through specific receptor(s) on target cells. This notion is supported by the result that HNP-induced migration of both T cells and iDCs is inhibitable by pretreatment of the target cells with PTX (Table 2) , indicating that HNP uses G_i protein-coupled receptor(s). Along similar lines, human ß defensins use CC chemokine receptor 6 as their receptor [²⁰ ] and plant defensins also interact with specific receptors on the target cells [⁴³ ]. Although both HNP and human ß defensins selectively chemoattract human immature DCs, HNP does not use CC chemokine 6 as a receptor (data not shown). This is not surprising given the fact that HNP and human ß defensins are selectively chemotactic for naive and memory CD4⁺ T cells, respectively. Obviously, it is important to identify and/or clone the receptor(s) of HNP in order to gain a deeper understanding of the biology and roles in adaptive immunity of HNP.

 
The authors wish to thank N. Dunlop for technical assistance, and Drs. J. M. Wang and R. D. Mellon for critical review of the manuscript. De Yang is supported in part by a fellowship from the Office of International Affairs, National Cancer Institute (NCI), National Institutes of Health (NIH). Oleg Chertov is funded in part by NCI, NIH contract No. N01-CO-56000. The support of the laboratory manager Ms. C. Fogle and secretarial assistance of Ms. C. Nolan is gratefully appreciated.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The publisher or recipient acknowledges right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

Received December 24, 1999; revised February 11, 2000; accepted February 14, 2000.

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