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Institute for Experimental Immunology, University Hospital, Zurich, Switzerland
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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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Three modes of Ab production, natural or spontaneous, T independent (TI),3 and T dependent (TD), potentially play roles in the protection against hematogenically spreading pathogens. Natural Abs representing the natural B cell repertoire are spontaneously, constitutively secreted without specific stimulation mainly by peritoneal B-1 cells (3, 4) and therefore represent a first line of defense against various pathogens (5). Specific B cells are activated in two different ways in vivo. Repetitively arranged Ags, such as haptenated synthetic polymers and neutralizing determinants of viruses (6), or polyclonal B cell activators, such as LPS, do not need second signals provided by cognate helper cells to induce B cell responses (6, 7, 8, 9). TI B cell activation has been correlated with antigenic structure (6, 10). For example, low density haptenated beads act as TD Ags, whereas haptenated beads at high density acted as TI Ags. Using linear polymers or viruses, the two-dimensional spacing of 5–10 nm has been shown to be optimal for TI induction of B cells (6, 11, 12). Bacteria or viruses often directly elicit strong TI Ab responses (13).
B cell activation by T cell-dependent Ags and generation of B cell memory requires two signals; the first signal is mediated by the occupied B cell receptor, and the second signal is usually provided by Th cells (14, 15). The actual priming of naive T cells is mediated by dendritic cells and probably by macrophages (16, 17). For the generation of TD humoral immune responses against proteins, adjuvants and booster immunizations are needed to obtain high Ab titers (18).
During hematogenic spread of an infection the host has to eliminate large quantities of Ag quickly to prevent the spread of the pathogen to peripheral vital organs. As a consequence, high titers of neutralizing Abs have to be elicited rapidly before or at the time the pathogen is reaching systemic circulation. Because induction of T help requires 4–6 days (19, 20, 21), early TI Ab responses might be crucial for survival. Therefore, the present study evaluated the role and induction requirements of TI and TD Ab responses in controlling viremia and in host protection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 and BALB/c mice were purchased from the Institute for Laboratory Animals (Veterinary Hospital, Zurich, Switzerland). CBA/xid and CBA/N controls were purchased from Harlan (Bicester, U.K.). Experiments were performed in a conventional mouse house facility, and mice were used at 6–12 wk of age.
Viruses and viral Ags
Vesicular stomatitis virus (VSV) Indiana (VSV-IND; Mudd-Summers isolate) and VSV New Jersey (VSV-NJ; Pringle isolate) were originally obtained from Dr. D. Kolakovsky (University of Geneva, Geneva, Switzerland) and were grown on BHK21 cells. Lymphocytic choriomeningitis virus (LCMV)-WE was originally obtained from Dr. F. Lehmann Grube (Heinrich Pette Institute, Hamburg, Germany) and was propagated on L929 fibroblast cells. Poliovirus stock solutions of serotype II were obtained from the Swiss Serum and Vaccine Institute (Bern, Switzerland). Inactivated poliovirus vaccine containing all three major serotypes (Salk, formaldehyde fixed) was purchased from BERNA (Bern, Switzerland). Recombinant baculoviruses expressing the glycoprotein of VSV (VSV G) and the nucleoprotein of LCMV (LCMV-NP) were gifts from Dr. D. H. L. Bishop, NERC Institute of Virology (Oxford, U.K.). They were derived from nuclear polyhedrosis virus and were grown at 28°C in Spodoptera frugiperda cells in Spinner cultures (22).
VSV and poliomyelitis virus neutralization assay
Serum from immunized mice was prediluted 40-fold in MEM containing 2% FCS. Serial 2-fold dilutions were mixed with equal volumes of VSV (500 PFU/ml) and incubated for 90 min at 37°C in an atmosphere with 5% CO2. One hundred microliters of the serum-virus mixture was transferred onto Vero cell monolayers in 96-well plates and incubated for 1 h at 37°C. The monolayers were overlaid with 100 µl of DMEM containing 1% methylcellulose and incubated for 24 h at 37°C. The overlay was flicked off, and the monolayer was fixed and stained with 0.5% crystal violet. The highest dilution of serum that reduced the number of plaques by 50% was taken as the titer. To determine IgG titers, undiluted serum was pretreated with an equal volume of 0.1 M 2-ME in saline. Poliovirus neutralization assays were performed similarly, but samples were prediluted 1/20 (23).
LCMV-NP-specific ELISA
We used an ELISA with the following steps: 1) coating with baculovirus-derived LCMV-NP (1 µg/ml); 2) blocking with 2% BSA (Fluka, Buchs, Switzerland) in PBS; 3) addition of 10-fold prediluted sera, titrated 1/3 over 12 dilution steps; 4) detection with IgM- or IgG-specific HRP-labeled goat anti-mouse Abs (0.5 µg/ml; Southern Biotechnology Associates, Birmingham, AL); and 5) addition of substrate 2,2'-azino-bis[3-ethylbenzthiazoline-6-sulfonate] (Roche, Mannheim, Germany) and H2O2 (Fluka). Plates were coated overnight at 4°C; all other incubations were conducted for 60–90 min at room temperature. Between incubations, plates were washed three times with PBS containing 0.05% Tween 20. OD was measured at 405 nm in an ELISA reader, and Ab titers were determined as the serum dilutions yielding an absorption of twice background levels.
In vivo CD4+ T cell depletion
Mice were treated i.p. on days -3 and -1 before infection with 1 mg of anti-CD4 mAb YTS191.6 (24). This treatment completely abrogates the switch from IgM to IgG and depletes CD4+ Th cells to below the detection level by FACS analysis (not shown).
Immunohistochemistry
Freshly removed organs were immersed in HBSS and snap-frozen in liquid nitrogen. Tissue sections 5 µm thick were cut in a cryostat, placed on siliconized glass slides, air-dried, fixed with acetone for 10 min, and stored at -70°C. Staining for VSV Ag or VSV-specific B cells was performed as previously described (25).
Splenectomy and intrasplenic/intra-lymph node injections
After ether anesthesia was administered to the mice, spleens were prepared for splenectomy, and the afferent and the efferent blood vessels were coagulated with a heated needle. Similarly, intrasplenic injections or injections directly into a lymph node were given in ether anesthesia after preparation of the spleen or mesenteric lymph nodes. The peritoneal cavity was closed with a silk suture, and the skin was stapled.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice were infected with different doses of replicating or
nonreplicating virus or with recombinant viral protein to analyze the
Th cell (CD4+ T cell) dependence of the resulting
Ab response. Experiments were performed in C57BL/6 and BALB/c mice
depleted of CD4+ T cells by repetitive injection
of CD4+ T cell-depleting Abs (24)
(Fig. 1
) or in T cell-deficient nude mice
(not shown, but yielding comparable results). This protocol resulted in
CD4+ T cell levels below the detection limit by
FACS analysis, and the efficiency of depletion was confirmed by a
complete block of the switch to IgG in treated animals (not shown). The
level of neutralizing IgG (distinguished from IgM by reduction with 0.1
M 2-ME, an unequivocal means of destroying IgM (26)) on
days 6 and 8 after immunization was at least 4-fold (=
2log2 steps) lower than that of total Ig (data
not shown), indicating that the Abs measured until day 8 largely
represented neutralizing IgM.
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, top row) with the
noncytopathic arenavirus LCMV (Fig. 1A), the highly
cytopathic rhabdovirus VSV (Fig. 1B), recombinant vaccinia
virus expressing the glycoprotein of VSV (Vacc VSV G; Fig. 1C), or poliomyelitis virus (Fig. 1E) elicited
IgM Ab responses that were largely independent of
CD4+ Th cells (anti-NP of LCMV Abs was
assessed by ELISA; VSV-, Vacc VSV G-, or poliomyelitis virus-specific
Abs were tested in neutralization assays). In contrast, a low dose
infection (Fig. 1, middle row) with these viruses led to a
largely T-dependent Ab response. These results were confirmed in mice
immunized with recombinant baculovirus-derived VSV proteins (Fig. 1D, VSV G protein) in which i.v. injection of 20 µg (Fig. 1D, top panel) or 1 µg (Fig. 1D,
middle panel) lead to a TI or TD Ab response,
respectively.
Most viruses and bacteria infect hosts via peripheral routes, often via
mucosal surfaces and not directly i.v. (with the exception of
arthropode-borne viruses (1), septicemias, or pyemias).
Therefore, an s.c. route of infection or immunization was evaluated for
the induction of TI Ab responses. Interestingly, Ab responses after
s.c. injection of a high infectious dose of VSV and poliomyelitis virus
or a high dose of a VSV model Ag were dependent on the presence of
CD4+ T cells (Fig. 1, bottom row).
Surprisingly, high doses of poliomyelitis virus failed to directly
elicit an Ab response after s.c. injections (not shown); however, after
s.c. injection in IFA inducing and providing efficient T help
(14), neutralizing Ab responses became detectable.
VSV and poliovirus exhibit their neutralizing determinants in a repetitive form (1, 11). In contrast, VSV protein or LCMV-NP released from infected cells forms micelles with a low degree of organization (27), and Vacc VSV G proteins are only expressed in the lipid bilayer membrane of infected cells without any strict organization (28). The results presented so far suggest that although the structure of the Ag plays a role (6, 12, 13) (see below), the type of Ab response to these various Ags depends crucially on 1) the infectious dose and 2) the route of infection or immunization used, independently of the structure of the immunizing agents. Thus, the structure of an infectious pathogen alone is not sufficient to predict the T dependence of an Ab response, and both infection kinetics and routes of a pathogen are apparently of great importance.
Therefore, the influence of dose on T dependence of Ab responses was
evaluated in more detail for TI-1 and TI-2 types of responses. TI Ab
responses can be separated into TI-1 and TI-2 Ab responses in mice
lacking the Bruton’s tyrosine kinase (xid mutation)
(29). Similarly, B cells of X-linked agammaglobulinemia
(agammaglobulinemia Bruton) patients, the human counterpart of the xid
mutation, are unable to react against certain TI Ags (30).
In xid mice, TI-1 Ags elicit normal IgM Ab responses after
CD4+ T cell depletion (29). In
contrast, TI-2 Ab responses are dependent on bystander help, and
therefore CD4+ T cell depletion in xid mice leads
to an impaired Ab response (29, 31, 32). The
xid and CBA/N control mice, either
CD4+ T cell depleted or left untreated (Fig. 2), were immunized i.v. with titrated
doses of infectious VSV. They revealed a TI-1 Ab response with 
2
x 107 PFU (Fig. 2, A and
D), a TI-2 Ab response with 5 x
105 PFU (Fig. 2, B and E),
and a TD Ab response with 
104 PFU (Fig. 2, C
and F). Thus, the i.v. dose of virus was key in determining
whether one and the same Ag was a strong TI-1 Ag, a weak TI-2 Ag, or
even strictly dependent on cognate T help.
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The finding that not only the infectious dose by itself but also
the route of Ag administration determine the mode of the B cell
activation suggested that dependence on T help is determined by the
amount of Ag reaching secondary lymphoid organs. To reduce efficient Ag
trapping to the spleen after systemic infection or immunization i.v.,
mice were splenectomized. Interestingly, i.v. infection of
splenectomized C57BL/6 mice with live VSV (Fig. 3, A1 and
A2) or with Vacc VSV G (Fig. 3, A3 and A4)
led to a delayed and reduced IgM response that, unexpectedly and in
contrast to that in unmanipulated control mice, was largely dependent
on T help, as documented by the susceptibility of Ab responses to
CD4+ T cell depletion and the delay of the Ab
response in splenectomized, compared with control, mice (Fig. 3, A1 vs A2 and
A3 vs A4,
respectively). The residual Ab titer induced in CD4+ T
cell-depleted splenectomized mice may be a consequence of T help
provided by 
T cells (33) or may reflect some
trapping of Ag in lymph nodes.
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B) or with inactivated
poliomyelitis virus (Fig. 3C). The nonreplicating Ag failed
to elicit Ab responses in splenectomized mice (Fig. 3, B and
C). These results are reminiscent of earlier experiments
that have shown that splenectomy completely blocks the Ab response to
certain nonreplicating Ags (35, 36). The present results
further support the view that live replicating pathogens provide IL
environments that enhance T help (34). Splenectomy,
therefore, did not block IgM production, but changed the mode of B cell
activation from a TI Ab response to a TD Ab response (Fig. 3, A1–A4). The
capacity to mount B cell responses independent of T help was not a
unique feature of the spleen. Injection of 5 x
106 PFU of live VSV directly into the mesenteric
lymph nodes of splenectomized and anti-CD4-treated animals primed B
cells largely without T help (Fig. 3D) compared with Ab
responses after i.v. infection of CD4+ T
cell-depleted and splenectomized C57BL/6 mice (Fig. 3A2). In contrast to earlier observations
with nonreplicating model Ags (37), our results indicate
that all secondary lymphoid organs (lymph nodes or spleen) allow the
induction of a TI Ab response if high amounts of Ag reach these
tissues. However, under physiological conditions, only the spleen is
able to efficiently filter Ag out of the circulation to trap sufficient
amounts of Ag for a T-independent Ab response. In contrast, and
importantly, comparable amounts of Ag injected s.c. apparently failed
to reach peripheral lymph nodes, probably via dendritic cells
(16), in a sufficient dose and adequate manner to activate
B cells without T help. Role of Ag structure
So far, our results indicate that TI Ab responses are determined
by Ag dose and localization. Earlier studies have suggested a role of
Ag structure (i.e., rigidly repetitive vs monomeric) on the induction
of TI Ab responses (6, 12, 38). We therefore
quantitatively compared the efficiency of VSV virions (exhibiting a
highly organized, rigidly repetitive, neutralizing determinant on the
intact virus) and VSV G protein preparation (where micelles show only a
low degree of organization) in the induction of a neutralizing Ab
response (Fig. 4A). The
concentration of VSV particles in the used virus preparation was
determined by electron microscopy. One infectious plaque-forming unit
analyzed by a plaque forming assay on Vero cells corresponded to 
10
viral particles counted by electron microscopy (not shown). Since the
number of glycoprotein per virion is about 1300 (1), the
amount of VSV glycoprotein per plaque-forming unit of VSV could be
calculated in micrograms of VSV glycoprotein. In
CD4+ T cell-depleted mice VSV glycoprotein
expressed on formalin-inactivated, and therefore nonreplicating, VSV
particles induced Ab responses with 1000 times lower Ag doses than a
recombinant VSV G protein preparation (Fig. 4A). For this
comparison both Ag forms were injected directly into the spleen to
overcome the possibility that VSV virus particles and VSV G protein
might be filtrated with different efficiencies to secondary lymphoid
organs. These results confirmed that the structure of the Ag also plays
an important role in the induction of TI Ab responses. However, in a
viral infection, but also for active immunizations, as shown in Figs. 1 and 2, the infection route and kinetics seem to be the more critical
parameters determining the early TI Ab responses.
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In the infections and immunizations tested here, TI or TD Ab
responses were induced with all infectious pathogens tested dependent
upon immunization dose and route. What, then, is the biological
relevance of TI Ab responses compared with TD Ab responses? VSV
infection of mice causes paralysis and death if the virus reaches
neuronal tissues (11, 39), and protection against a
primary infection strictly depends on rapid generation of neutralizing
Abs (9). We therefore analyzed the relevance of a TI Ab
response in VSV infection. Splenectomized C57BL/6 mice, which cannot
mount a TI Ab response (Fig. 3, A1 and
A2), failed to control virus titer in the
blood after an i.v. infection with 2 x 108
PFU VSV (Fig. 4B), had detectable infectious virus in the
brain (Fig. 4B), and developed paralytic disease (Table I). In contrast, after a high dose
infection (2 x 108 PFU) s.c., a route of
infection that fails to systematically spread at high levels (Fig. 4B), but that also only induces a delayed TD Ab response
(Fig. 1A), all mice survived (Table I). These results
indicate that a TI Ab response is crucial for the organism to cope with
rapidly replicating pathogens that spread via blood circulation at high
titers.
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The implied importance of Ag trapping and accumulation in spleen
after i.v. immunization was evaluated by immunohistochemistry.
Infection with VSV offers the unique possibility that VSV Ag and
VSV-specific B cells can be stained well in histological sections
(25). Infection of mice with a high dose of VSV that
elicits TI Ab responses (Fig. 1A) revealed the presence of
Ag in the splenic marginal zone on day 2 after infection (after
infection with 108 PFU VSV; Fig. 5A). By 48 h after
infection, B cell foci had formed around the splenic marginal zone
(after infection with 106 (not shown) and
108 PFU of VSV; Fig. 5C);
subsequently, specific plasma cells were observed in the red pulp (Fig. 5E). VSV-specific plasma cells are characterized by an
intense intracytoplasmic staining, whereas VSV-specific B cells
expressing the specific receptor mainly on their cell surface are only
surface stained. After infection i.v. with 104 or
102 PFU of VSV, doses that elicited TD Ab
responses (Fig. 1A), VSV-specific B cells or plasma cells
were observed only on day 6 and later (Fig. 5, D and
F), and no Ag could be stained in the splenic marginal zone
(Fig. 5B). The first appearance of VSV-specific B cells
after a low dose infection occurred indeed largely only in T cell areas
of the spleen where efficient T help can be provided (Fig. 5F). Note that by days 6–8 after infection comparable Ab
titers were mounted independently of the infectious dose (Fig. 1), and
comparable numbers of plasma cells were induced (Fig. 5, E
and F) after a high or a low dose infection with VSV. Thus,
B cell foci around the marginal zone seem to correlate with, and are
probably a consequence of, early Ag trapping by splenic marginal zone
macrophages and represent a histological correlate of an early TI Ab
responses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4–6 days to mount a
specific Th cell response (21), the Ab kinetics may be too
slow to protect the host from the consequences of a high-dose systemic
infection. TI Abs can fulfill this early function efficiently.
Two interlinked parameters determine the induction of TI-1, TI-2, or TD
Ab responses: 1) Ag dose and 2) efficient recruitment of Ag to
secondary lymphoid organs (summarized as the model in Fig. 4C). Thus, the general rules for B cell induction are
similar to those for T cells, where the amount of Ag present in
secondary lymphoid organs over a given time period are the key to their
induction (41, 42). The role of Ag structure in B cell
induction is probably linked to both Ag amount and cross-linking of B
cell receptors. The latter is only possible if a high Ag density is
present on splenic marginal zone macrophages. Therefore, cross-linking
of B cell receptors is achieved either by high amounts of monomeric Ag
trapped on marginal zone macrophages leading to a high density of
epitopes on their surface or by fewer multimeric repetitive particles
leading to a focal, but also locally dense, concentration of Ag.
Complement and natural Abs seem to be involved in Ag trapping and
targeting to marginal zone macrophages (43). Marginal zone
B cells have been shown previously to be involved in TI Ab responses
(44, 45). Therefore, if the pathogen itself exhibits the
neutralizing epitope in a repetitive form, B cell receptor
cross-linking is mediated more easily, and the dose of Ag required in
secondary lymphoid organs to induce TI Ab responses is lower.
Nevertheless, after infections with highly repetitive Ags, an efficient
Ag pooling to the splenic marginal zone is still the key to inducing a
TI B cell response.
Most infectious pathogens enter the host via mucosal surfaces (46) and not at high doses directly via blood. Pathogens then spread to local lymph nodes and start a local immune response before systemic spread (2). The findings presented here offer an explanation for the increased susceptibility of splenectomized patients to selected systemic infections. In accordance with our viral models, patients after splenectomy, with functional aspleny (e.g., sickle cell anemia) or infants with an immature splenic marginal zone (47) are not able to mount TI Ab responses. As a consequence, they are susceptible predominantly to pathogens that are initially controlled on mucosal surfaces without inducing a potent systemic humoral immune response but that suddenly may lead to a massive hematogenic spread, i.e., Haemophilus influenzae, Streptococcus pneumoniae, and Enteroviridae. Additionally, these patients cannot be vaccinated with TI polysaccharide vaccines.
Of course, efficient B cell induction is also a goal of any improved design of vaccines. Virus-like particles have been shown to be one efficient means to elicit TI Ab responses (48, 49). Taken together, these and our results suggest that application of Ags at sufficiently high doses directly into secondary lymphoid organs or in formulations that will be efficiently trapped to and filtered out in secondary lymphoid organs should rapidly induce highly efficient protective B cell responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Adrian F. Ochsenbein, Institute for Experimental Immunology, Schmelzbergstrasse 12, CH-8091, Zurich, Switzerland.
3 Abbreviations used in this paper: TI, T cell independent; TD, T cell dependent, LCMV, lymphocytic choriomeningitis virus; LCMV-NP, LCMV nucleoprotein; VSV, vesicular stomatitis virus; VSV-IND, VSV Indiana serotype; VSV G, VSV glycoprotein; Vacc VSV G, recombinant vaccinia virus expressing VSV G.
Received for publication January 28, 2000. Accepted for publication April 4, 2000.
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References |
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-producing T cell-dependent antibody isotype switching in the absence of germinal center formation during virus infection. Proc. Natl. Acad. Sci. USA 95:1160.This article has been cited by other articles:
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