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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-07-2305.
CHEMOKINES
From the Department of Microbiology and Immunology,
Morehouse School of Medicine, Atlanta, GA; Department of Microbiology
and The Immunobiology Vaccine Center, University of Alabama at
Birmingham; and Laboratory of Immunology, National Institute on Aging,
Gerontology Research Center, Baltimore, MD.
Macrophage inflammatory protein-1 Early-acting innate effector molecules are required
to signal the host of potentially lethal agents for protection. In this regard, intestinal epithelial cells produce inflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor- MIP-1 We have previously demonstrated that lymphotactin and RANTES
(regulated on activation normal T cells expressed and secreted) enhance mucosal and systemic immunity when nasally coadministered with
a protein Ag.30,31 These previous studies clearly suggest that chemokines may be major regulatory molecules facilitating the
induction of adaptive mucosal immunity. The current study seeks to
identify the effects of MIP-1 Reagents
Mice and immunizations
Sample and tissue collection Fecal samples were weighed and dissolved in PBS containing 0.1% sodium azide (eg, 1 mL per 100 mg of fecal pellet). Following suspension by vortexing for 10 minutes, fecal samples were centrifuged and supernatants were collected for analysis. Nasal and vaginal cavities were rinsed 3 times with 50 µL PBS. Blood samples were collected by tail vein bleeding, and serum was obtained following centrifugation. Serum and mucosal secretions were collected on days 0, 7, 14, and 21 for OVA-specific Ab analysis by enzyme-linked immunosorbent assay (ELISA). Mice were killed by CO2 inhalation 1 week after the last immunization to quantify the OVA-specific Ab-forming cells (AFCs) and T-cell responses present in immune compartments.OVA-specific Ab detection by ELISA Fecal and serum sample levels of OVA-specific Abs were measured by ELISA, as previously described.30 Briefly, 96-well Falcon 3912 flexible ELISA plates (Fisher Scientific, Pittsburgh, PA) were coated with 100 µL of 1 mg/mL OVA in PBS overnight at 4°C and blocked with 1% BSA (Sigma) in PBS (B-PBS) for 3 hours at room temperature. Individual samples (100 µL) were added and serially diluted in B-PBS. After overnight incubation at 4°C and 3 washes using PBS containing 0.05% Tween 20 (PBS-T), titers of immunoglobulin M (IgM), IgG, or IgA were determined by the addition of a 0.33 µg/mL horseradish peroxidase (HRP)-conjugated goat antimouse µ, , or  heavy chain-specific antisera (Southern Biotechnology Associates, Birmingham, AL) in B-PBS-T. Similarly, 100 µL
biotin-conjugated rat antimouse 1 (G1-7.3 at 12.5 ng/mL), 2a
(R19-15 at 125 ng/mL), 2b (R12-3 at 12.5 ng/mL), 3 (R40-82 at 50 ng/mL), and  (G1-7.3 at 1.25 µg/mL) (PharMingen, San Diego, CA)
heavy chain-specific mAbs were used to determine IgG subclass and IgE
isotype titers.30 After incubation and wash steps, 100 µL of 0.5 µg/mL HRP-antibiotin Ab (Vector Laboratories, Burlingame,
CA) in B-PBS-T or 500 ng/mL poly-HRP80 streptavidin (Research
Diagnostics, Flanders, NJ) in Poly-HRP Diluent (Research
Diagnostics) was added to IgG subclass or IgE detection wells,
respectively, and incubated for 3 hours at room temperature. Following
incubation, the plates were washed 6 times and the color reaction for
ELISA was developed by adding 100 µL of 1.1 mM
2,2'-azino-bis(3)-ethylbenzthiazoline-6-sulfonic acid (Sigma)
in 0.1 M citrate-phosphate buffer (pH 4.2) containing 0.01%
H2O2 (ABTS solution). End-point titers were
expressed as the reciprocal log2 of the highest dilution,
which indicated an optical density that was 415 nm (OD415)
of at least 0.1 OD unit above the OD415 of negative
controls after a 20-minute incubation.30
Cell isolation Single-cell suspensions of spleen, Peyer patches, nasal tract, and cervical lymph nodes were prepared by aseptically removing tissues and then passing them through a sterile wire screen. Lower respiratory tract tissues were excised, minced, and further disrupted by stirring in collagenase type IV (Sigma) in RPMI 1640 (collagenase solution) during incubation at 37°C.30 After removal of Peyer patches, the small intestine was cut into 1 cm strips and stirred in PBS containing 1 mM EDTA (ethylenediaminetetraacetic acid) at 37°C for 30 minutes. Next, intestinal lamina propria lymphocytes were isolated by digesting tissue in the collagenase solution for about 45 minutes with stirring at 37°C. Lymphocytes were further purified using a discontinuous Percoll (Pharmacia, Uppsala, Sweden) gradient, collecting at the 40% to 75% interface.30 Cell suspensions were washed twice in RPMI 1640. Lymphocytes were maintained in complete medium, which consisted of RPMI 1640 supplemented with 10 mL/L nonessential amino acids (Mediatech, Washington, DC), 1 mM sodium pyruvate (Sigma), 10 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) (Mediatech), 100 U/mL penicillin, 100 µg/mL streptomycin, 40 µg/mL gentamycin (Elkins-Sinn, Cherry Hill, NJ), 50 µM mercaptoethanol (Sigma), and 10% fetal calf serum (FCS) (Atlanta Biologicals, Norcross, GA). T-cell fractions were obtained by passing single-cell suspensions over nylon wool for 1 hour at 37°C (more than 95% purity).IgA, IgM, and IgG enzyme-linked immunospot (ELISPOT) analysis An ELISPOT assay was used to detect total or OVA-specific AFCs.30 In brief, 96-well Millititer HA nitrocellulose-based plates (Millipore, Bedford, MA) were coated with 100 µL of 1 mg/mL OVA in PBS, PBS only (negative control), or 0.5 µg/mL goat antimouse Ig (H+L) polyclonal Ab (positive control) (Southern Biotechnology Associates) and incubated overnight (12 hours) at 4°C. Subsequently, wells were blocked with B-PBS for 2 hours and washed with complete media. Whole cells were added to wells in duplicate at 1 × 106/mL, 5 × 105/mL, and 1 × 105/mL concentrations in complete medium and incubated for 6 hours at 37°C in 5% CO2. After washing with PBS-T, individual AFCs were detected with HRP-labeled goat antimouse µ,, or chain-specific Abs (1 µg/mL) (Southern
Biotechnology Associates), visualized by adding
3-amino-9-ethylcarbazole (AEC) buffer (Moss, Pasadena, MD), and counted
using a dissecting microscope (SZH Zoom Stereo Microscope System;
Olympus, Lake Success, NY).
Ag-specific T-helper cell responses Purified T cells were cultured at a density of 5 × 106/mL with 1 × 106/mL T cell-depleted and irradiated 30 Gy (3000 rad) splenic feeder cells in complete medium containing OVA (1 mg/mL) at 37°C in 5% CO2. T cells were cultured in 96-well round-bottom plates (Corning Glass Works, Corning, NY) to determine Ag-specific proliferative responses. After 3 days of culture, cells were pulsed with 0.5 µCi (0.0185 MBq) methyl-3H-thymidine (Amersham Life Sciences, Arlington Heights, IL) per well for 18 hours. Cells were harvested on glass microfiber filter paper (Whatman, Clifton, NJ), and radioactivity levels were obtained by liquid scintillation counting.Effects of MIP-1 and MIP-1 . A
class II-restricted OVA peptide containing amino acids 323 to 339 (50 µg/mL) was used to activate primary OVA-specific T-cell
receptor (TCR) transgenic CD4+ T cells from
DO11.10 mice.32 Lymphocytes were also cultured with
optimal doses of concanavalin A (ConA; 5 µg/mL) or antimouse CD3 mAb (10 µg/mL-coated plates) as positive controls or alone as
negative controls. After incubation for 2 days, cells were stained with
phycoerythrin (PE)-conjugated rat antimouse CD28, CD30, CD37, CD80,
CD86, CD154, or CD153 (PharMingen) and Cy5-conjugated CD4, and/or B220,
fluorescein isothiocyanate (FITC)-conjugated MAC-1 and/or CD8 mAbs
(PharMingen) for 30 minutes with agitation. Lymphocytes were
then washed with fluorescence-activated cell sorter (FACS)
buffer (PBS with 1% BSA) and fixed in 2% paraformaldehyde in PBS and
analyzed by flow cytometry using a FACSCaliber (Becton Dickinson,
San Jose, CA).
Cytokine analysis by ELISA For the assessment of cytokine production, 800 µL of culture supernatants from 24-well flat bottom plates (Corning Glass Works) was harvested after 2 days of incubation. The T-helper (Th) cytokines, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-, IFN-, and
granulocyte-macrophage colony-stimulating factor (GM-CSF), in
cell culture supernatants were determined by ELISA following the
manufacturer's instructions (E-Biosciences, San Diego, CA). The IL-5
cytokines in culture supernanatants were determined as described
previously by Lillard et al.30 Briefly, Falcon 3912 Microtest plates (Fischer Scientific) were coated with 100 µL of 2.5 µg/mL rat antimouse IL-5 (PharMingen) in 0.1 M
bicarbonate buffer (pH 9.5) overnight at 4°C and blocked with 3% BSA
in PBS at room temperature for 3 hours. Next, serially diluted
recombinant murine cytokines as standards (PharMingen) or cultured
supernatant samples were added in duplicate and incubated overnight at
4°C. The plates were washed with PBS-T and incubated with 0.2 µg/mL
biotinylated secondary murine cytokine detection Abs (PharMingen) in
B-PBS-T at room temperature for 3 hours. After washing with PBS-T and
PBS, wells were incubated for 2 hours in 100 µL of 0.5 µg/mL
peroxidase-conjugated antibiotin Ab (Vector Laboratories) and developed
with ABTS solution, as described above. The cytokine ELISA assays were
capable of detecting 15 pg/mL IFN-; 5 pg/mL IL-2, IL-4, and IL-5;
100 pg/mL IL-6; and 200 pg/mL IL-10.
In vitro T-cell proliferation assay Proliferating T lymphocytes were labeled with 5-bromo-2'-deoxy uridine (BrdU, Roche Diagnostics, Dusseldorf, Germany); subsequently, BrdU incorporation was detected using a scanning multiwell spectrophotometer (SpectraMax 250 ELISA reader, Molecular Devices, Sunnyvale, CA). In brief, after 2 days of culture, cells at a density of 1 × 106/mL were transferred in polystyrene 96-well plate (Corning Glass Works). An aliquot of 10 µL BrdU labeling solution (10 µm/mL) per well was added and incubated for 18 hours at 37°C in a humidified atmosphere containing 5% CO2. The cells were then fixed and incubated with 100 µL nuclease in each well for 30 minutes at 37°C. The cells were washed with complete media and again incubated with BrdU solution for 30 minutes at 37°C. The incorporation was developed in ABTS solution, and the optical density was read at 450 nm.Cytotoxic T lymphocyte (CTL) analysis The CD8+ T-cell subset from the cervical lymph nodes, Peyer patches, and spleen were isolated and purified as described above and restimulated ex vivo with the class I-restricted peptide of OVA257-264 (SIINFEKL) for 5 days with syngeneic EL4 feeder cells.33 The cytotoxic T lymphocyte (CTL) response was determined by a 4-hour 51Cr release assay using E.G7.OVA target cells.34Statistics The data are expressed as the mean ± 1 SEM and compared using a 2-tailed Student t test or an unpaired Mann-Whitney U test. The results were analyzed using the Statview II statistical program (Abacus Concepts, Berkeley, CA) for Macintosh computers and were considered statistically significant if P values were less than .05. When cytokine levels were below the detection limit (BD), they were recorded as one half the lower detection limit (eg, 50 pg/mL for IL-6) for statistical analysis.
MIP-1 and MIP-1 that
would affect Ag-specific serum Ab responses. For this purpose, mice
were nasally administered 3 times at weekly intervals with OVA (75 µg) in the presence of increasing concentrations of the 2 chemokines
(eg, 0.0, 0.01, 0.1, 1.0, and 5.0 µg). Accordingly, we analyzed
OVA-specific Ab isotypes and IgG subclasses in sera and mucosal
secretions. Significant titers of OVA-specific Ab responses were
elicited when mice were given a 1.0 µg dose of MIP-1 or MIP-1,
and the Ab responses were not further increased when chemokine doses
were increased (data not shown). Therefore, a dose of 1 µg MIP-1
or MIP-1 was used for subsequent in vivo experiments. Mice nasally
immunized 3 times with OVA plus 1 µg MIP-1 or MIP-1 displayed
significantly increased Ag-specific serum IgG Ab levels (Figure
1). Serum IgE and IgA Ab responses were
noted only in mice that received MIP-1 but not MIP-1 (Figure 1).
Both molecules clearly exerted different effects on serum IgG subclass
responses. The humoral adjuvant activity of MIP-1 induced
significant increases in anti-OVA IgG1 and IgG2b Ab titers followed by
IgG2a and IgG3, while MIP-1 only induced IgG1 and IgG2b Ab responses
(Figure 2).
MIP-1 or MIP-1 could promote mucosal secretory IgA Ab responses. Analysis of OVA-specific S-IgA Ab responses in mucosal secretions revealed significant S-IgA Ab titers in fecal extracts as
well as vaginal and nasal washes of mice nasally immunized with OVA
plus MIP-1 or MIP-1 (Table 1).
These results were further confirmed by analysis of OVA-specific AFCs
in cells isolated from mucosal and systemic tissues. Mice that received
OVA alone did not display substantial Ag-specific AFCs in any of the
tissues analyzed (Figure 3). Both
MIP-1 and MIP-1 increased OVA-specific IgM and IgG AFCs in
splenic and respiratory tract cell isolates but not in intestinal
lamina propria-derived cells (Figure 3). We noted the presence of
significant IgA AFCs in tissues from mice immunized with MIP-1 but
limited IgA AFC generation by MIP-1 (Figure 3). These results
suggest that the nasal delivery of MIP-1 or MIP-1 enhanced
OVA-specific peripheral IgG Ab responses, while MIP-1 significantly
stimulated S-IgA Abs.
Proliferation and cytokine secretion by MIP-1 and MIP-1 differentially regulated mucosal and
systemic Ab responses, we next examined whether the differences in
their effects could be attributed to their ability to differentially promote Th1- versus Th2-type cytokine responses. The CD4+ T
cells isolated from the lower respiratory tract, Peyer patches, cervical lymph nodes (CLNs), or spleens of mice immunized with OVA in
the presence of MIP-1 or MIP-1 exhibited marked increases in
OVA-specific proliferative responses in comparison with
CD4+ T cells derived from control mice that received OVA
alone (Figure 4). In addition, these
chemokines enhanced the splenic-, Peyer patch-, lower respiratory
tract-, and CLN-derived Th cell-derived responses to in vitro
restimulation with OVA. In fact, CD4+ T cells from these
inductive lymphoid tissues of mice immunized with either MIP-1 or
MIP-1 exhibited greater IFN- secretion when compared with
CD4+ T cells from control mice given OVA only (Figure
5). IFN- responses were always higher
in groups that received MIP-1. On the other hand, MIP-1 promoted
higher levels of Th2 cytokine responses (ie, IL-4, IL-5, and IL-6) by
ex vivo-restimulated OVA-specific T cells (Figure 5). Thus, MIP-1
and, to a lesser degree, MIP-1 promote IFN- and Th1-type
responses, while IL-4 and Th2-type responses were especially induced
by MIP-1.
MIP-1 and/or MIP-
support CTL responses. For this purpose, CLN, Peyer patch, and spleen CD8+ T cells were assessed for their cytotoxic T-cell
activity. No specific CTL response was noted in CLN, Peyer patch, or
spleen cells from control mice immunized with OVA only or MIP-1 plus OVA. In contrast, cells from mice that received the MIP-1 plus OVA
showed dramatic increases in the percent cell lysis of the H-2b-restricted EG7.OVA tumor cell line34;
interestingly, increased CTL responses were seen in cells isolated from
both mucosal and systemic immune compartments (Figure
6).
Effects of MIP-1
and MIP-1, we assessed their potential to modulate the expression of
costimulatory molecules (ie, CD80, CD86, and CD40) on B cells and that
of corresponding receptors (ie, CD28 and CD154/gp39) on T cells.
Results depicted in Figure 7 clearly show
that MIP-1
MIP-1 and MIP-1
effects on distinct regulation of costimulatory signals, we
next assessed their potential to modulate the expression of receptors for costimulatory molecules expressed by T cells. MIP-1
significantly increased the expression of CD28 and CD154 (ie, CD40L and
gp39) by OVA-stimulated CD4+ T cells; on the other hand,
MIP-1 promoted only modest increases in CD154 expression by
OVA-stimulated CD4+ T cells (Figure
8). MIP-1 did not affect CD28
expression by either resting or OVA-stimulated CD4+ T
cells. The same pattern of regulatory effects by MIP-1 and MIP-1
were observed by CD8+ T cells. In contrast with the effect
on CD4+ T cells, MIP-1 failed to stimulate CD40L
expression by Ag-stimulated CD8+ T cells (data not
shown).
We finally investigated the effect of MIP-1
The spectrum of mucosal cells expressing MIP-1 Immunization of mice with OVA and MIP-1 IFN- The precise cytokine signals required for S-IgA production are not
completely understood, and studies support that both Th1- and Th2-type
cell-derived cytokines are important for S-IgA.49-51 We
have previously shown that chemokines like lymphotactin and RANTES also
induce S-IgA.30,31 Clearly, serum and mucosal Ag-specific Ab responses were enhanced by MIP-1 We have also shown that the cytokine responses promoted by these
chemokines, particularly MIP-1 Cytokines produced by CD4+ T cells after mucosal
administration of MIP-1 MIP-1 CD154 (ie, gp39 or CD40L) is considered a major determinant in
the outcome of T cell-B cell interactions.53 CD40L
stimulation can also drive B-cell activation and IgA
production.54,55 The generation and activation of
cell-mediated immunity often depends on the availability of and
help from CD4+ T cells and requires CD154
interactions.56,57 We show for the first time that
MIP-1 CD28 also supplies a coactivation signal for T-cell
activation.58,59 Stimulation through CD28 acts in concert
with the signals provided by Ag recognition, which result in IL-2
production and subsequent cell division.60 CD28 is also
required for mucosal immunity and T cell-mediated
immunity.60,61 We have previously shown that RANTES acts
as a mucosal adjuvant partly through CD28 up-regulation.31
In the current study, we show that MIP-1 4-1BB is preferentially expressed by Th1-type T cells, and naive T
cells can be led to differentiate to Th1-type T cells after 4-1BB and
CD28 stimulation.37,62 4-1BB is also necessary for optimal
induction, amplification, and persistence of CTL
responses.39 MIP-1 Our results show that both Th1- and Th2-type pathways can be induced by
mucosally administered MIP-1
This paper benefited from many fruitful conversations with members of the Morehouse School of Medicine, the University of Alabama at Birmingham Immunobiology Vaccine Center, and the National Institutes of Health's National Institute on Aging.
Submitted August 1, 2002; accepted September 4, 2002.
Prepublished online as Blood First Edition Paper, September 12, 2002; DOI 10.1182/blood-2002-07-2305.
Supported in part by the United Negro College Fund (UNCF)-Merck Postdoctoral Fellowship, Foundation for Digestive Health and Nutrition Research Scholar Award, and National Institutes of Health grants RR03034, GM08248, DK58967, AI18958, AI43197, DC04976, and P30 DK54781.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jerry R. McGhee, Department of Microbiology, 845 19th St South, BBRB 761, Birmingham, AL 35294; e-mail: mcghee{at}uab.edu; and James W. Lillard Jr, Department of Microbiology, 720 Westview Dr, Atlanta, GA 30310; e-mail: lillard{at}msm.edu.
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and MIP-1
differentially mediate mucosal and
systemic adaptive immunity
Top
Abstract
Introduction
/
) or 1.0 µg MIP-1
)
in PBS. The data presented are the mean Ab titers ± SEMs of 3 separate experiments. ELISA determined the distribution of OVA-specific
serum and fecal Ab titers on day 21. Asterisks indicate statistically
significant differences (P < .05) from Ab titers of mice
immunized with OVA alone.
) or MIP-1
) or MIP-1
) in PBS. One week after the last immunization, spleen-, Peyer
patch-, and CLN-derived CD8+ lymphocytes were purified and
restimulated ex vivo with OVA peptide 257-264 (SIINFEKL) for 5 days
with syngeneic EL4 cells in complete medium. Experimental groups
consisted of 5 mice, and studies were repeated 3 times. The cytotoxic
response was determined by 4-hour 51Cr release against
E.G7.OVA or OVA peptide 257-264 (SIINFEKL) pulsed EL4 cells. Data shown
are mean values of triplicates obtained at varying effector-target
ratios as indicated.
