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*
Division of Dermatology and
Department of Microbiology and Immunology, University of California School of Medicine, Los Angeles, CA 90024;
Section of Dermatology, University of Southern California School of Medicine, Los Angeles, CA 90033;
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Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
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Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Whereas previous work establishes the function of CD1 in Ag recognition by T cells, the critical question of the role of this system in host defense against infectious diseases in vivo has not been examined. As an initial step toward defining the in vivo relevance of this system, we have studied the involvement of CD1 in the immune response to Mycobacterium leprae, the causative agent of leprosy. Infection with this organism provides an opportunity to study the human immune response to a mycobacterial pathogen in situ, since much of the pathology is localized to the skin, where the relevant lesions can be easily sampled. Furthermore, leprosy presents as a spectrum in which clinical disease correlates with different levels of responsiveness to M. leprae (11). At one pole of the spectrum are patients with strong cell-mediated immunity to M. leprae and a localized form of disease, which constitutes tuberculoid leprosy. At the opposite pole are patients with lepromatous leprosy, who lack effective cell-mediated immunity and suffer from a more disseminated form of the disease. The existence of this spectrum provides the opportunity to assess immunoregulatory mechanisms that may operate in vivo in humans to determine the ultimate outcome of the immune response to infection.
In the present study, we have examined the expression of CD1 proteins in the cutaneous lesions of patients with these two polar forms of human leprosy. Our results demonstrated a strong correlation between the expression of three different CD1 proteins (i.e., CD1a, -b, and -c) known to be involved in the presentation of mycobacterial lipid Ags, and the presence of effective host immunity to M. leprae. CD1 expression in tuberculoid lesions was shown to be primarily restricted to a mature dendritic cell (DC)4 population, and in vitro functional studies revealed that DCs bearing the phenotype found in tuberculoid lesions were extremely efficient at presenting mycobacterial lipid Ags to CD1b-restricted T cells. These results support the hypothesis that lipid Ag presentation by CD1 plays a beneficial role in host immunity to microbial pathogens in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leprosy patients were recruited on a volunteer basis from the ambulatory population seen at the Dermatology Clinics at the University of Southern California Medical Center, Los Angeles. Clinical classification of patients with symptomatic M. leprae infection was done according to the criteria of Ridley and Jopling (11). Skin biopsy specimens (6 mm diameter) containing both epidermis and dermis were obtained by standard punch technique following informed consent. Blood samples for isolation of PBMC were obtained by venipuncture from leprosy patients and from healthy volunteer laboratory personnel who served as control subjects. PBMC were isolated using Ficoll-Hypaque gradient centrifugation (Ficoll-Paque; Pharmacia, Uppsala, Sweden), according to the supplier’s instructions.
Ags and Abs
Extracts of M. leprae and Mycobacterium tuberculosis (strain H37Ra; Difco, Detroit, MI) were prepared by probe sonication, as described (7). Tetanus toxoid was obtained from the Massachusetts Public Health Biological Laboratory (Boston, MA). The following Abs were used for flow cytometry and immunohistochemical studies: P3 (IgG1 control (12)), OKT6 (anti-CD1a (13)), 4A7.6.5 (anti-CD1b (14)), 10C3 (anti-CD1c (1)), W6/32 (anti-HLA-A,B,C (15)), DK22 (anti-HLA-DR; Dako, Carpenteria, CA), B10A-1 (anti-CD83 (16)), 3C10 (anti-CD14; American Type Culture Collection (ATCC), Manassas, VA), and MAC-1 (anti-CD11b; ATCC).
Immunohistochemical studies of CD1 expression in leprosy skin lesions
Biopsy specimens were embedded in OCT medium (Ames, Elkhart, IN) and snap frozen in liquid nitrogen. Sections (3–5 µm thick) were acetone fixed and blocked with normal horse serum before incubation with the mAbs for 60 min, followed by biotinylated horse anti-mouse IgG for 30 min. Primary Ab was visualized with the ABC Elite system (Vector Laboratories, Burlingame, CA), which uses avidin and a biotin-peroxidase conjugate for signal amplification. ABC reagent was incubated for 30 min, followed by the addition of substrate (3-amino-9-ethylcarbazole) for 10 min. Slides were counterstained with hematoxylin and mounted in glycerin-gelatin. The level of CD1-positive cells in dermal granulomas was quantitated by calculating the percentage of positive cells based on the total number of cells (i.e., hematoxylin-stained nuclei) within the granuloma.
Two-color immunofluorescence staining of cryostat sections
Double immunofluorescence was performed by serially incubating cryostat tissue sections with mouse anti-human mAbs of different isotypes (e.g., 4A7.6.5 (anti-CD1b, IgG2a), and either 3C10 (anti-CD14, IgG1) or B10A-1 (anti-CD83, IgG1)), followed by incubation with isotype-specific, fluorochrome (FITC or tetramethylrhodamine isothiocyanate (TRITC)-labeled goat anti-mouse Ig Abs (Southern Biotechnology, Birmingham, AL). Controls included staining with isotype-matched irrelevant Abs, as well as staining with 4A7.6.5, 3C10, or B10A-1, followed by secondary Abs mismatched to the primary Ab isotype to demonstrate the isotype specificity of the secondary labeled Abs. Images were obtained using a Zeiss Axiophot microscope.
In vitro culture of CD1-expressing monocyte-derived DCs
CD1 expression on monocytes was induced in vitro with a
combination of 200 U/ml of human rGM-CSF and 100 U/ml of human rIL-4
for 72 h, as described (4, 17). Cell surface expression of CD1 was
determined by flow cytometry using CD1-specific mAbs, as done
previously (4). Further differentiation of CD1+
monocyte-derived cells into CD83+ DCs was achieved by
addition of TNF-
(Endogen, Woburn, MA; 1000 U/ml, or indicated
concentration), as described (16). In some experiments, heat-killed
mycobacterial sonicates or purified Escherichia coli LPS
(Sigma, St. Louis, MO) were added instead of TNF- for the final 3
days of culture. Cells were harvested using incubation in PBS/0.5 mM
EDTA to detach adherent cells, and analyzed by flow cytometry or
irradiated (5000 rad) and used as APCs.
T cell lines and proliferation assays
CD1b-restricted T cell lines DN1 and LDN4 (4, 6) and HLA-DR-restricted T cell clone SP-F3 (18) were maintained by serial antigenic stimulation in IL-2-supplemented medium, as detailed previously (7). For measurement of Ag-specific proliferation, 5 x 104 T cells were cultured with varying numbers of irradiated (5000 rad) allogeneic CD1+ APC in 0.2 ml culture medium in the presence or absence of bacterial Ags for 4 days in flat-bottom microtiter plate wells at 37°C in a 5% CO2 incubator. Cells were pulsed with [3H]thymidine (1 uCi/well) and harvested 4–6 h later for liquid scintillation counting.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunohistochemistry was performed on biopsy specimens of skin
lesions from seven patients with tuberculoid leprosy and six with
lepromatous leprosy using mAbs specific for CD1a, -b, and -c. In all
samples from tuberculoid patients, these CD1 proteins were strongly
expressed by large dendritic mononuclear cells distributed throughout
areas of mononuclear cell infiltration and clustered at the periphery
of well-formed dermal granulomas (Fig. 1
,
D–F). Expression of CD1 proteins in surrounding areas of
nonlesional skin was comparable with that described previously for
normal skin, in which the dermis contains only rare CD1c+
DCs that weakly express CD1a and lack detectable CD1b (19). CD1a
expression was also observed in the epidermis of biopsies from
tuberculoid patients (Fig. 1D), where its distribution on
epidermal Langerhans cells was comparable with that of normal skin
(20).
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, A–C). The only prominent CD1 staining consistently observed
in lepromatous samples was in the epidermis, where CD1a+
Langerhans cells were observed at levels similar to that of normal skin
(Fig. 1A). Quantitation of CD1+ cells as a
percentage of total cells within the dermal granulomas showed that
cells expressing each form of CD1 were present at approximately a
10-fold greater average frequency in tuberculoid as compared with
lepromatous lesions (Fig. 2). Thus, CD1
proteins were expressed in the lesions of a subset of leprosy patients
in a manner that correlated with the presence of an effective
cell-mediated immune response to the pathogen.
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, G–I). Thus, the appearance of CD1 proteins within
leprosy lesions could be correlated temporally with the acquisition of
immunity to the pathogen.
Although CD1a, -b, and -c proteins were absent or only weakly expressed
in the lesions of lepromatous patients, they could be induced in vitro
by a combination of GM-CSF and IL-4 on blood monocytes from these
patients, as previously shown for normal subjects (4, 17). In fact, the
percentages of monocytes showing CD1 surface expression after cytokine
induction in PBMC from lepromatous patients showed a range similar to
that for identically cultured monocytes from tuberculoid patients (Fig. 3, A and B).
Although there were no significant differences in the mean percentages
of CD1a-, b-, or c-positive monocytes between the two patient groups,
both groups showed a trend toward a lower percentage of
CD1+ monocytes under these conditions when compared with
normal controls (Fig. 3B). These differences achieved
statistical significance in several instances (e.g., for CD1a in the
tuberculoid patients, and for CD1b and -c in the lepromatous patients),
and could be indicative of a subtle defect or alteration in the
circulating monocytes of patients with both clinical forms of leprosy.
However, the ability to similarly induce CD1 expression on mononuclear
cells derived from both patient groups in vitro indicated that the
virtual absence of these proteins from the dermal granulomas of
lepromatous leprosy patients was probably not the result of a
generalized or primary defect affecting the CD1 system.
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To define the lineage of the CD1+ cells observed in
tuberculoid lesions, we first assessed whether these were tissue
macrophages by double staining with Ab to CD1b and to the
monocyte/macrophage markers CD14 (Fig. 4A) or CD11b (not shown).
Although many cells positive for either CD14 or CD11b could be
demonstrated, these only rarely showed detectable staining for CD1b
(<1% positive). In contrast to the failure of CD1b+ cells
to colabel with Abs to CD14 or CD11b, nearly 100% of these cells were
stained with a mAb specific for CD83 (Fig. 4B), a cell
surface protein expressed at high levels only by DCs (22). These
results identified the predominant cell type expressing CD1b in
tuberculoid leprosy lesions as a DC, which was distinct from the tissue
macrophages that were also abundant in these lesions.
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The presence of a prominent population of DCs expressing CD1
in the dermal lesions of tuberculoid leprosy subjects strongly
suggested that these would be likely to function as APCs for M.
leprae-specific CD1-restricted T cells, which have been previously
isolated from similar lesions (6, 8). This possibility was assessed
using an in vitro system to measure APC function. The relatively small
amounts of tissue obtained from biopsy samples of tuberculoid leprosy
lesions precluded the direct isolation of
CD1+CD83+ APCs from these tissues for
functional studies. However, recently developed methods for cultivation
of DCs has allowed the generation of large numbers of CD83+
DCs suitable for in vitro studies of APC function (16). Thus, treatment
of human peripheral blood monocytes with GM-CSF plus IL-4 for 3 to 7
days resulted in the surface expression of high levels of CD1a, -b, and
-c proteins (4, 17). Subsequently, these cells were maintained in the
same medium either without or with various doses of TNF- for an
additional 48 h to produce CD83- and
CD83+ monocyte-derived DCs (16).
As previously reported (16), addition of TNF- to monocytes following
culture for several days with GM-CSF plus IL-4 led to a dose-dependent
induction of CD83 on the cell surface, as shown by flow cytometry (Fig. 5A). Interestingly, cell
surface levels of CD1a, -b, and -c were either unchanged or slightly
decreased by TNF- treatment compared with paired cultures maintained
only in GM-CSF plus IL-4 (Fig. 5B). This was in contrast to
MHC class II molecules (HLA-DR), which were expressed at increased
levels on the cell surface after TNF- treatment (Fig. 5B), as previously described by others (16, 23). A similar
transition to a CD1+CD83+ phenotype was also
observed after exposure of CD1+CD83-
monocyte-derived DCs for 48 h to a M. leprae sonicate
or to purified E. coli LPS (Fig. 5C).
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A).
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B). Overall,
these results supported the hypothesis that DCs bearing the mature
CD83+ phenotype observed in tuberculoid leprosy lesions in
vivo function as effective APCs for CD1-restricted T cell responses,
and are superior to their CD83- counterparts for lipid Ag
presentation to at least some CD1-restricted T cells. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The absence of CD1 expression in lepromatous lesions was probably not due to an intrinsic defect of the CD1 system, since these proteins could be up-regulated to similar levels on peripheral blood monocytes from patients with either tuberculoid or lepromatous disease. Instead, the pattern of CD1 expression seemed to reflect the known cytokine expression within these lesions from the different clinical forms of human leprosy. For example, mRNA for GM-CSF, a major inducer of CD1 on monocyte-derived cells in vitro, has been shown to be abundantly transcribed in tuberculoid, but not in lepromatous leprosy lesions (25, 26). Conversely, IL-10, which is abundantly transcribed in lepromatous but not tuberculoid lesions (25, 26), is a potent inhibitor of CD1 expression induced by GM-CSF (27). These findings suggest that the local cytokine milieu is an important determinant in the process of recruitment or differentiation of the CD1+ cells identified in tuberculoid lesions and reversal reactions.
The regulation of CD1 expression on DCs in leprosy lesions appears to differ significantly from the regulation of MHC-encoded Ag-presenting molecules in such lesions. Thus, three studies that have examined the expression of MHC class II molecules in lepromatous lesions have detected expression of these molecules (28, 29, 30), in contrast to what appears to be a complete absence of CD1a, -b, and -c in the lepromatous lesions we have studied. In fact, studies that have examined this issue using immunohistochemical methods similar to those used in our analysis of CD1 expression have not detected a noticeable difference in MHC class II expression between tuberculoid and lepromatous lesions (29, 30). To the best of our knowledge, expression of MHC class I molecules has not yet been studied in leprosy, and therefore, conclusions cannot yet be drawn about the behavior of these Ag-presenting molecules compared with the CD1 proteins.
The CD83+CD14-CD11b-
phenotype of CD1+ cells within tuberculoid granulomas
strongly supports the classification of these cells as members of the
DC family. DCs are now regarded as the major stimulators of primary T
cell responses, as well as potent stimulators of memory responses (23, 31). They have recently been shown to be a major source of IL-12 that
leads to generation of Th1 responses (32), and can also produce an
array of other cytokines and chemokines (33). As such, their presence
within infected tissues of patients with strong cell-mediated immunity
to M. leprae is likely to stimulate responses that promote
effective control of the infection. As demonstrated previously (16) and
confirmed by the present work, the transition of
CD83-CD1+ monocyte-derived cells to
CD83+CD1+ DCs is stimulated by TNF-. Our
studies showed that this transition also occurred after exposure of
CD83-CD1+ monocyte-derived cells to
mycobacterial extracts or LPS. These observations suggest a mechanism
for linking the response of the innate immune system to the acquired T
cell-mediated response through the induction of a population of potent
APCs.
Although the molecular signals controlling the development of a mature
DC phenotype in response to bacterial products are not yet established,
it is well known that bacterial preparations such as those used in this
study are potent inducers of TNF- secretion by monocyte lineage
cells (34, 35). Thus, an autocrine stimulation pathway can easily be
visualized, in which TNF- acts as the final common mediator of CD83
induction for all of the conditions examined in our studies.
Preliminary experiments also indicate that the ingestion of live
mycobacteria by monocytic cells can serve as a trigger for the
transition to a CD1+CD83+ DC (S. Stenger and R.
Modlin, unpublished data). This is supported by a recent report
describing activation of human peripheral blood-derived DCs by
infection with live M. tuberculosis, which was associated
with increased surface expression of costimulatory molecules (CD54,
CD40, and CD80) and secretion of inflammatory cytokines (TNF-, IL-1,
and IL-12) (36). That direct mycobacterial infection of DCs may be
required for inducing this transition in tuberculoid leprosy lesions in
vivo is an intriguing possibility, and could explain why only a
minority of the monocyte-derived cells within these lesions acquire a
CD1+CD83+ phenotype. However, this possibility
is complicated by the recent finding that infection of monocyte-derived
DCs in vitro with live M. tuberculosis causes
down-regulation of CD1a, -b, and -c mRNA transcripts and a loss of
surface expression by the infected APC within 48 h (37). This
suggests that if DC maturation is induced by direct mycobacterial
infection, the CD1+CD83+ phenotype may persist
only transiently. Alternatively, M. leprae may not possess
this ability to down-regulate CD1 expression, or additional factors
could exist in vivo that prevent CD1 down-regulation in infected DCs.
Based on our studies of the APC function of CD83+
monocyte-derived DCs in vitro, it appears likely that the
CD1+CD83+ cells identified in tuberculoid
leprosy lesions are potent APCs for CD1-restricted T cell responses.
Previous studies have shown that human monocyte-derived APCs that have
been induced to undergo maturation by exposure to TNF- are extremely
efficient stimulators of T cells in mixed lymphocyte reactions,
probably at least in part because of the up-regulation of costimulatory
molecules (particularly CD86 (B7.2) (16)). However, it has also been
found that exposure of monocyte-derived DCs to TNF- mobilizes the
majority of MHC class II molecules to the cell surface. This is
associated with a reduction in the ability of such mature DCs to take
up and present new Ags via the MHC class II pathway (23), a finding
that is recapitulated in our experiments using a well-characterized
HLA-DR-restricted tetanus toxoid-specific T cell clone (Fig. 6).
In contrast, for two CD1b-restricted T cell lines responsive to
different mycobacterial lipid Ags, we observed that Ag-specific
proliferation was more efficiently stimulated by CD83+
cells compared with their CD83- counterparts. Although
more data will be required to determine whether this finding can be
generalized to the majority of CD1b-restricted T cell responses, our
results suggest that the regulation of Ag presentation through the CD1
pathway may be fundamentally different from regulation of the MHC class
II pathway. The mechanism accounting for the enhanced presentation of
newly encountered Ags by mature DCs to CD1b-restricted T cells is not
yet known. However, this may relate to superior costimulation by DCs
after treatment with TNF-, or to enhanced uptake or processing of
mycobacterial lipid Ags through pathways that may be regulated
independently of the Ag-capturing machinery used by the MHC class II
pathway. Whereas TNF- treatment caused an increase in surface
expression of MHC class II consistent with the mobilization of class II
proteins from the endocytic system to the cell surface, no such
increase was seen for CD1a, -b, or -c proteins. Previous studies have
shown that the mechanisms controlling the transport of CD1 and MHC
class II proteins into endocytic compartments are different (38, 39, 40),
and this may account for the contrasting effects of TNF- on the
surface expression and Ag-presenting function of these molecules.
Although additional experiments will be required to resolve the precise
mechanisms involved, our current results provide further evidence for
functional divergence between the MHC class II and CD1 pathways in the
presentation of exogenous foreign Ags.
The presence of CD1-expressing cells within cutaneous leprosy lesions,
combined with the previous isolation of CD1-restricted T cells from the
skin of a subject responsive to M. leprae (6, 8), suggests
an important role for CD1 in immunity to M. leprae.
CD1-restricted T cells specific for mycobacteria display cytotoxic
activity against infected cells (41), have direct bactericidal effects
on released bacilli (41), and produce IFN-
and other proinflammatory
cytokines (6). The importance of the CD1 system in immunity to
extremely resistant intracellular pathogens such as mycobacteria may
relate strongly to its unique ability to present a set of nonprotein
microbial lipid Ags that are entirely distinct from peptide Ags
recognized by MHC-restricted T cells. Because of the highly conserved
structure of many microbial lipids, and the nonpolymorphic structure of
the CD1 proteins themselves, these Ags are appealing candidate vaccine
subunits. The studies of human leprosy presented in this work indicate
that the activity of this pathway correlates with effective immunity to
a mycobacterial pathogen, and underscore the importance of
incorporating our growing knowledge of the CD1 system into efforts to
develop improved vaccines and immunotherapies for human infectious
diseases.
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Acknowledgments |
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Footnotes |
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2 Current address: Service de Dermatologie, Hopital Edouard Herriot, Place d’Arsonval, 69437 Lyon, Cedex 03, France.
3 Address correspondence and reprint requests to Dr. Steven A. Porcelli, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Room 516B Smith Building, 1 Jimmy Fund Way, Boston, MA 02115. E-mail address:
4 Abbreviations used in this paper: DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; MFI, mean fluorescence intensity.
Received for publication June 8, 1998. Accepted for publication October 26, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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K. Hiromatsu, C. C. Dascher, K. P. LeClair, M. Sugita, S. T. Furlong, M. B. Brenner, and S. A. Porcelli Induction of CD1-Restricted Immune Responses in Guinea Pigs by Immunization with Mycobacterial Lipid Antigens J. Immunol., July 1, 2002; 169(1): 330 - 339. [Abstract] [Full Text] [PDF]
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 S.M. Rhind CD1--The Pathology Perspective Vet. Pathol., November 1, 2001; 38(6): 611 - 619. [Abstract] [Full Text] [PDF]
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 B.N. Lambrecht, J-;B. Prins, and H.C. Hoogsteden Lung dendritic cells and host immunity to infection Eur. Respir. J., October 1, 2001; 18(4): 692 - 704. [Abstract] [Full Text] [PDF]
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C. W. Cutler, R. Jotwani, and B. Pulendran Dendritic Cells: Immune Saviors or Achilles' Heel? Infect. Immun., August 1, 2001; 69(8): 4703 - 4708. [Full Text] [PDF]
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S. M. Hayes and K. L. Knight Group 1 CD1 Genes in Rabbit J. Immunol., January 1, 2001; 166(1): 403 - 410. [Abstract] [Full Text] [PDF]
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P. A. Sieling, S. A. Porcelli, B. T. Duong, F. Spada, B. R. Bloom, B. Diamond, and B. H. Hahn Human Double-Negative T Cells in Systemic Lupus Erythematosus Provide Help for IgG and Are Restricted by CD1c J. Immunol., November 1, 2000; 165(9): 5338 - 5344. [Abstract] [Full Text] [PDF]
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M. Mempel, B. Flageul, F. Suarez, C. Ronet, L. Dubertret, P. Kourilsky, G. Gachelin, and P. Musette Comparison of the T Cell Patterns in Leprous and Cutaneous Sarcoid Granulomas : Presence of V{alpha}24-Invariant Natural Killer T Cells in T-Cell-Reactive Leprosy Together with a Highly Biased T Cell Receptor V{alpha} Repertoire Am. J. Pathol., August 1, 2000; 157(2): 509 - 523. [Abstract] [Full Text] [PDF]
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P. A. Sieling, M.-T. Ochoa, D. Jullien, D. S. Leslie, S. Sabet, J.-P. Rosat, A. E. Burdick, T. H. Rea, M. B. Brenner, S. A. Porcelli, et al. Evidence for Human CD4+ T Cells in the CD1-Restricted Repertoire: Derivation of Mycobacteria-Reactive T Cells from Leprosy Lesions J. Immunol., May 1, 2000; 164(9): 4790 - 4796. [Abstract] [Full Text] [PDF]
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U. E. Schaible, K. Hagens, K. Fischer, H. L. Collins, and S. H. E. Kaufmann Intersection of Group I CD1 Molecules and Mycobacteria in Different Intracellular Compartments of Dendritic Cells J. Immunol., May 1, 2000; 164(9): 4843 - 4852. [Abstract] [Full Text] [PDF]
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F. M. Spada, E. P. Grant, P. J. Peters, M. Sugita, A. Melian, D. S. Leslie, H. K. Lee, E. van Donselaar, D. A. Hanson, A. M. Krensky, et al. Self-Recognition of Cd1 by {gamma}/{delta} T Cells: Implications for Innate Immunity J. Exp. Med., March 20, 2000; 191(6): 937 - 948. [Abstract] [Full Text] [PDF]
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C. C. Dascher, K. Hiromatsu, J. W. Naylor, P. P. Brauer, K. A. Brown, J. R. Storey, S. M. Behar, E. S. Kawasaki, S. A. Porcelli, M. B. Brenner, et al. Conservation of a CD1 Multigene Family in the Guinea Pig J. Immunol., November 15, 1999; 163(10): 5478 - 5488. [Abstract] [Full Text] [PDF]
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