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Department of Immunology, Scripps Research Institute, La Jolla, CA 92037
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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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The trafficking pattern of arriving DCs and their precise location at specific times during their maturation is of principal importance for productive interactions with T and B lymphocytes (2, 3, 4). Presumably, DCs that enter the spleen through venous sinuses receive signals attracting them to the white pulp and are then further directed to specific locations in the white pulp where they initiate immune responses.
Signals directing DC migration and residence may be both soluble and via cell-cell interaction. The nature and source of some of the soluble signals have recently been identified (5, 6). For example, plt mice lack detectable expression of secondary lymphoid tissue chemokine (SLC) and have decreased levels of EBV-induced molecule 1 ligand chemokine (ELC) (7). Because plt animals harbor diminished numbers of DCs and T lymphocytes in their peripheral lymphoid organs, it has been suggested that DCs and T lymphocytes that express the CCR7 receptor for these chemokines utilize this pathway for homing. Cell-cell interactions are also critical in the regulation of the immune response. Molecular interactions can send survival or apoptotic signals as well as stabilize cell-cell interactions. For example, ligation of receptor activator of NF-kB (RANK) and CD40 on DCs by receptor activator of NF-kB ligand (RANKL) and CD40L on T lymphocytes can lead to up regulation of adhesion and costimulatory molecules and the generation of anti-apoptotic signals in the DC (8, 9). One model proposes that in the course of the immune response, myeloid DCs in the marginal zone receive maturation or activation signals that cause the DC to modulate surface expression of homing molecules and APC activity. These fully matured DCs migrate into the T area where DCs may receive necessary survival signals during interaction with circulating T cells (10). Collaboration between DCs and B lymphocytes has also been demonstrated. In vitro generated DCs promote the proliferation of naive and CD40-activated B cells and produce factors that induce differentiation of activated B cells into plasma cells (11, 12, 13). It is unknown whether B cells have an effect on DC responses or survival.
To determine whether soluble or interactive signals from lymphocytes
influenced the presence and distribution of the distinct splenic DC
subsets, we examined splenic DC populations in mice lacking T or B
lymphocytes. In this way, we focused on the contribution of these
specific cell types rather than defects in mice bearing undefined
mutations or pleiotropic effects caused by gene knockouts that affect
multiple lineages. Using mice that lacked mature B cells
(IgMtm-/-), mature 
ß T cells
(TCR--/-), mature B, and mature T cells
(RAG-1-/-), we examined the microanatomical
location of CD11c+ splenic DCs as well as the
presence of phenotypically distinct subsets of splenic DCs. The
implications of these findings are discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR--/- mice and
RAG-1-/- mice were purchased from The Jackson
Laboratory, Bar Harbor, ME. IgM-/- mice were
generously provided by Dr. Norman Klinman, Scripps Research Institute.
All mice were maintained in the Scripps Research Institute animal
colony under specific pathogen-free conditions in accordance with
National Institutes of Health and institutional guidelines.
Antibodies
The following reagents were used to label for either FACS or
immunohistology: anti-CD86, anti-CD8a, anti-MAdCAM-1,
anti-B220, anti-TCR-ß, streptavidin-PE, PharMingen, San
Diego, CA; 33D1 (anti-DC), N418 (anti-CD11c), American Type
Culture Collection, Manassas, VA; anti-follicular DC (FDC) clone
4C11, gift from Marie Kosco-Vilbois; NLDC145 (anti-DEC-205),
Accurate Chemicals, Westbury, NY; SER-4 (anti-metallophilic
macrophage), MOMA-2 (anti-metallophilic macrophage), ERTR9
(anti-marginal zone macrophage), Bachem, Torrance, CA; biotinylated
mouse anti-rat, biotinylated goat anti-Armenian hamster,
streptavidin-HRP, HRP-goat anti-Armenian hamster, HRP-goat
anti-rat, Jackson ImmunoResearch Laboratories, West Grove, PA;
FITC-goat anti-rat, Boehringer Mannheim, Mannheim, Germany;
avidin-biotin-glucose oxidase conjugate system, glucose oxidase
substrate system, Vector Laboratories, Burlingame, CA.
Immunohistochemistry
Cryostat sections (10 µm thick) were acetone fixed and air dried before rehydration. Sections were incubated for 30 min with PBS containing 1% BSA before incubation with the following: anti-mouse Abs, biotinylated secondary anti-Ig, streptavidin peroxidase. Peroxidase activity was visualized with 3-amino-9-ethylcarbazole substrate (Sigma, St. Louis, MO) according to the protocol provided by the manufacturer. For double labeling, peroxidase-labeled sections were again incubated for 30 min with PBS containing 1% BSA followed by labeling with anti-mouse Abs, appropriate biotinylated anti-Ig, and avidin-biotin-glucose oxidase conjugate. Bound glucose oxidase was visualized with reagents and protocols provided by the manufacturer (Vector Laboratories).
Reconstitution assays
Normal B220+ lymphocytes from spleen or lymph nodes were sorted and injected retroorbitally into B-deficient or normal hosts. Control animals received B220-, CD4+, and B220-CD8+ cells sorted from lymph node. In some experiments, B lymphocytes were isolated by depletion of CD11b+CD4+CD8+F480+CD3+ cells by Ab labeling followed by removal with anti-Ig magnetic beads. In each case, 10–20 million cells were transferred. Seven days after transfer, animals were sacrificed, and tissues were removed for histological examination or FACS analysis of isolated splenic DCs.
FACS analysis
DC were recovered from spleens by enzymatic digestion followed by isolation of low density cells (17). Enriched populations of cultured DCs were obtained by adherence of low density cells followed by overnight deadherence of mature DCs. For FACS phenotyping, cells were labeled with various anti-mouse Abs followed by FITC-anti-Ig. Identification of DCs was performed by counterstaining with PE-conjugated CD86.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We used a panel of mAbs to investigate the correlation between
splenic marginal zone organization and the localization of DCs. In the
normal mouse spleen, the majority of CD11c+ DCs
are found concentrated in two distinct areas within the white pulp: in
macrophage-free regions at the marginal zone border and in the T areas
as interdigitating cells (10) (Fig. 1
a).
Sialoadhesin+ marginal zone macrophages (MZM)
were often present as a sheath of single cells around the white pulp
with regular breaks occurring at areas enriched in T cells and DCs
(Fig. 1e). The MZM colocalized with another population of
marginal zone cells that expressed the lymphocyte homing receptor
MAdCAM-1 (14, 15, 16). Two-color immunohistochemistry
demonstrated that the MAdCAM-1+ splenic reticular
cells were distinct from the sialoadhesin+ MZM
(Fig. 1b).
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As in normal spleens, CD11c+ DC in
TCR-/ - mice found concentrated near the
marginal zone at breaks in the macrophage sheaths and in the T area of
the white pulp (Fig. 1
c). Marginal zone macrophages and
MAdCAM-1+ reticular cells were present at the
outer border of the white pulp in the same highly organized structures
observed in normal spleens (Fig. 1d). The DCs in both the T
area and marginal zone area took on an appearance that was more compact
than seen in normal spleens (Fig. 1e). The unusual
plaque-like appearance of T area DCs was likely due to the inability to
visualize individual DC bodies and dendritic processes that were
normally apparent when the DCs interdigitated between T lymphocytes.
Interestingly, the marginal zone appeared more heavily populated with
MAdCAM-1-expressing cells in T-deficient spleens than in normal spleens
(Fig. 1e). Nevertheless, despite these unusual aspects, it
was clear that DCs still arrived and resided in the appropriate non-B,
perivascular areas of the splenic white pulp and marginal zone quite
independent of mature T lymphocytes.
The spleens of B lymphocyte-deficient animals displayed several abnormalities involving macrophage and DC organization
The positioning of the marginal zone DCs in B-deficient mice
represented a major departure from normal architecture. Marginal zone
DCs were no longer sequestered into specific DC areas bordering the T
area. Instead, the DC areas encircled the T-containing white pulp (Fig. 1f). Another striking change was the near complete absence
of marginal zone macrophages and MAdCAM-1+ cells
(Fig. 1g). The few MZM and reticular cells were sometimes
colocalized at the marginal zone borders and appeared to align in a
network such as in the normal spleen. The MZM deficiency was confirmed
using ERTR9 and MOMA-2 Abs specific for marginal zone macrophages or
metallophilic macrophages, respectively (results not shown).
Importantly, despite the meager representation of those specific
marginal zone cells, there remained good segregation of white and red
pulp. T-rich areas were well defined, interdigitating DCs in the T
areas were easily identifiable and separate from marginal zone DCs, and
F4/80+ macrophages were restricted to areas
outside of the T area (not shown).
The white pulp of RAG-1-/- spleens consisted almost entirely of densely packed CD11c+ DCs
It was obvious that the DCs in RAG-1 knockout mice still received
their positional cues because they organized themselves around central
arterioles throughout the spleen. Similar to the situation in B-less
mice, marginal zone components were disrupted (Fig. 1i). The
DC areas were often associated with the few
MAdCAM-1+ cells also present in these spleens
(Fig. 1h). Sialoadhesin+ macrophages
were occasionally present but not aligned in any way representative of
a marginal zone. Evidently, CD11c+ DCs leave
venous sinuses, traverse to the vicinity of a central arteriole, and
generate white pulp areas in response to signals not derived from
mature lymphocytes. In the absence of lymphocytes, it was not obvious
whether there remained any true segregation of the two subsets as was
observed in normal spleens. This issue was addressed in a later
section.
B cell areas exert a shaping force on DC distribution
Our findings in B-deficient mice indicated that mature B
lymphocytes had a principal role in bringing about specific aspects of
splenic architecture. To confirm this, we adoptively transferred normal
splenic B cells into B lymphocyte-deficient animals. Seven days after
transfer, B lymphocytes were found in several B areas of the splenic
white pulp. DCs took on a more polar distribution next to the T area
(Fig. 2a) instead of the
circumferential distribution originally observed in B-deficient animals
(Fig. 2b). Strong MAdCAM-1 expression occurred only in those
tracts abutting the areas containing transferred B cells (Fig. 2a). MAdCAM-1 induction was not apparent in B-less animals
that received T cells only (Fig. 2b). Similarly, FDCs
appeared in the areas repopulated by transferred B cells (Fig. 2c) and not those that received only T lymphocytes (Fig. 2d). Despite the reestablishment of some aspects of the
splenic architecture in B cell recipients,
sialoadhesin+ MZM were not found in the spleen
(Fig. 2e). It is possible that the appropriate environment
existed in reconstituted mice, yet MZM recruitment could not occur
within the time frame examined. Others have reported that chemically
depleted MZM repopulate lymphoid organs only after 2–5 mo (17, 18). Spleens of RAG-/- mice
reconstituted with splenic B and T lymphocytes also reestablished a
more normal distribution of T area and marginal zone DCs, FDCs, and
marginal zone MAdCAM-1 expression, without MZM recruitment (not
shown).
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DCs released from the mouse spleen may be divided into several
subsets by their distinct surface Ag phenotypes. The two major
CD11c+ subpopulations identified are also
distinct by virtue of their microanatomical locations
(10). Myeloid DCs expressing macrophage markers such as
CD11b, CD16/CD32, and the DC-specific marker 33D1 correspond to the
marginal zone DCs described earlier. They are found primarily in the
area bordering the marginal zone and the white pulp (Fig. 3a). Interdigitating DCs,
alternatively called lymphoid DCs, bear the DEC-205 surface Ag and CD8,
but not 33D1 or any macrophage markers, and are located in the deep
cortex of the T area (Fig. 3a). CD11c+
DCs in the white pulp of RAG -/- spleens were
so densely packed that the distinction between the marginal zone subset
and the normally interdigitating subset was not apparent. We
investigated this issue using the anti-CD11c Ab, which reacts with
both DC subsets in the spleen, in combination with DEC-205, which
reacts with the lymphoid DC subset found in the T area. In this manner,
we revealed that the densely packed DCs in lymphocyte-deficient mice
still segregated according to subset. Reminiscent of the tight knot
seen in the T-deficient spleens (Fig. 3b),
CD11c+DEC-205+ lymphoid DCs
were tightly arranged around the arteriole in the center of the white
pulp of RAG-1-/- spleens (Fig. 3c).
A similarly compact sheath of
DEC-205-CD11c+ myeloid DCs
encircled the T area DCs. Immunostaining of serial sections revealed
that the rare MAdCAM-1+ reticular cells were
positioned between the two DC subsets (not shown). Thus, in the absence
of signals derived from mature T and B cells, DC subsets may enter and
localize appropriately within the splenic white pulp.
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All the factors that determine the DC localization are not known; hence, it is unclear whether there exists a relationship between the specific location of a subset and the survival of that subset in the tissue. We investigated whether the absence of specific leukocyte subsets and disruption of the DC-lymphocyte interaction and microanatomical location resulted in alteration of the relative numbers of specific subsets.
Of the fresh splenocytes released by collagenase digestion,
CD11c+ cells represent 1–2% of the cells or
1.5–2 million DCs (not shown). Of those, 
0.8–1.0 million were
recovered after enrichment by adherence and 10–15 h culture (Table I). In the cultured DC population,
8–10% of CD86high DCs were identified as
DEC-205+ lymphoid DCs (Fig. 4). The remainder were
33D1+DEC-205- myeloid DCs
(not shown). Surprisingly, in the absence of T cells, the number of
lymphoid DCs appeared unaffected, whereas there were slightly fewer
marginal zone DEC-205- DCs. T cell-deficient
spleens contained 1.2–1.5 million DCs of which 0.7–1.0 million were
recovered after culture (Table I). Of the cultured DCs, 12–14% were
DEC-205+ (Fig. 4b). The loss of
nonlymphoid DCs was even more pronounced in spleens of B-deficient
mice. In B cell receptor-deficient (BCR-) mice,
only 0.5–0.6 million DCs were recovered from cultured, adherent
splenocytes (Table I) and 17–19% of those were
DEC-205+ (Fig. 4c). DCs from B- and
T-deficient spleens were even further reduced in numbers.
CD11c+ cells constituted roughly 5% of freshly
isolated splenocytes which represented 0.6 million cells (not
shown). Of these, less than one-half were recovered after culture,
although 25–30% of the cultured DCs were
DEC-205+ (Fig. 4d). In each case, the
DC deficiency was due to a loss in 33D1+ myeloid
DCs, not DEC-205+ lymphoid DCs (Table I and
unpublished FACS results). Apparently, the
DEC-205+ DCs in T areas were not greatly affected
by the loss of mature T and B lymphocytes or marginal zone macrophages.
However, the extensive loss of certain marginal zone cells or total
cellularity of the spleen did correlate with a loss of marginal
zone DCs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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If resident and circulating lymphocytes were responsible for delivery of organizational and survival signals by splenic DCs, then lymphocyte-deficient mice should suffer profound defects in splenic DC populations. This was not the case. We found no deficit in numbers of lymphoid DCs, and only in mice that lacked B lymphocytes did there seem to be an impact on numbers of myeloid DCs. The separation of distinct DC subsets in the white pulp was not disrupted. In the absence of mature B and T lymphocyte populations, DCs enter the spleen from the blood, traverse along the length of the white pulp, and accumulate in discrete areas according to subset. Even in the case of RAG-1 knockout mice where all CD11c+ DCs resided in uniform DC areas of white pulp, it was shown that the DC subsets remained segregated. The DEC-205+ lymphoid DCs associated closely with the central arteriole and the myeloid DCs remained outside the lymphoid DC zone. Thus, the arrangement of splenic DC subsets in lymphocyte-deficient mice demonstrated clearly that in general, the homing instructions to DC areas were independent of lymphocytes.
Although the recruitment of DCs into the white pulp of the spleen and
segregation of subsets was not greatly impacted, some aspects of the
spatial arrangement of DC subsets were affected by the loss of
lymphocytes. The abnormal distribution may have occurred due to a loss
of cell volume. For example, in T lymphocyte-deficient mice, the white
pulp consisted primarily of B cells. As a result the T area DCs were
reduced to a compact plaque of cells. Similarly, the marginal zone area
DCs experienced greater than usual pressures excluding them from
regions adjacent to B areas resulting in a small patch of marginal zone
area DCs compacted to a higher cell density. In the converse situation,
B lymphocyte-deficient mice lacked the large B follicles that normally
drive the DCs into proscribed areas adjacent to the T cells. As a
result, when marginal zone DCs migrated to white pulp that lacked B
cells, the DCs remained fairly evenly dispersed around the T areas.
Another explanation for the abnormal distribution of DCs in these mice
may be altered chemotactic signals. Diminished chemokine levels in
B-deficient mice and strengthened chemotactic signals in white pulp of
T-deficient mice might result in a diffuse arrangement of myeloid DCs
in B-deficient mice and the compact arrangement in T-deficient mice.
Indeed, B lymphocytes are a source of macrophage inflammatory protein
(MIP)-1 and MIP-1ß, both of which are chemoattractants for
blood-derived DCs (19, 20, 21). Furthermore, if macrophages in
the marginal zone also bear receptors for these factors, then
macrophage-free areas would be the sites where factors would be
accessible to myeloid DCs.
B lymphocyte transfer into B-deficient mice partly restored some but not all aspects of normal architecture. In B-deficient mice or in mice that received B cells by adoptive transfer 1–2 wk before examination, marginal zone macrophages were not detected with Abs specific for sialoadhesin (SER-4), marginal zone metallophils (MOMA-1), or MZM (ERTR-9). FDCs were restored in B areas of B cell recipients. MAdCAM-1 expression by reticular cells was reestablished in marginal zones bordering all areas populated with transferred B lymphocytes. It is likely that lymphotoxin expression by B lymphocytes is responsible for marginal zone MAdCAM-1 expression in the spleen (22). As predicted, the B-containing white pulp had the effect of sequestering the DCs into a more polar distribution. These observations suggest that B follicles have a significant effect on the DC distribution even though other elements are the principal issuers of DC guidance signals. The nature of the contribution of B lymphocytes to the organization of DCs remains unclear.
We report a correlation between marginal zone disorganization and
decreased numbers of marginal zone DCs. One possible explanation for
the loss of myeloid DCs is that these DCs are sensitive to changes in
chemokine levels brought about by the absence of B cells. Indeed,
myeloid DCs reportedly undergo apoptosis if they do not receive
maturational or survival signals (23). We and others have
found decreased levels of SLC, ELC, and B lymphocyte chemoattractant in
lymphocyte-deficient mice (Ref. 24 and unpublished results). In
this case, it is possible that other factors are also present in
diminished concentrations at an increasing distance from the white pulp
source. Consequently, the myeloid DCs in the marginal zone border would
not receive appropriate levels for survival or maturation. Attractive
candidate factors to provide such a signal are B cell-derived
chemokines MIP-1 and MIP-1ß (19, 20, 21).
Our observations support models that depict non-bone marrow-derived endothelial cells as the source of important organizational signals. We provide evidence that factors that direct DC migration to splenic white pulp are present independently of mature lymphocytes. The task ahead lies in identifying the key factors and the specific cell type responsible. Several reports have shown that the relevant source is in the T area in the vicinity of the central arteriole (7, 24). The efferent lymphatic vessels of the spleen girdle the central arteriole in the deep cortex of the white pulp. Factors produced by endothelial cells or macrophages resident in these structures may be responsible in part for directing the DCs to the T area. For example, endothelial cells can produce a number of chemokines including RANTES (25) and MCP-1 (26) for which DCs express receptors. It had also been shown that MIP-3ß expression was restricted to T areas and that only mature, activated DCs had a chemotactic response to this chemokine (1, 27). Lymphatic endothelial cells in the vicinity of the central arteriole may express this or other factors chemotactic for DCs. Indeed, two recent reports indicate a role for stromal cell-derived SLC and ELC in recruitment of DCs to T zones in peripheral lymphoid organs, although the mechanisms of their actions are not well understood (5, 6, 7). The identification of other ligands and receptors that promote DC chemotactic activity in the spleen will shape future models.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mary Crowley or David Lo, Scripps Research Institute, IMM-25, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cells; BCR, B cell receptor; SLC, secondary lymphoid tissue chemokine; ELC, EBV-induced molecule 1 ligand chemokine; MZM, marginal zone macrophages; FDC, follicular DC.
Received for publication January 5, 1999. Accepted for publication August 23, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L. Fan, C. R. Reilly, Y. Luo, M. E. Dorf, and D. Lo Cutting Edge: Ectopic Expression of the Chemokine TCA4/SLC Is Sufficient to Trigger Lymphoid Neogenesis J. Immunol., April 15, 2000; 164(8): 3955 - 3959. [Abstract] [Full Text] [PDF]
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