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. Author manuscript; available in PMC: 2011 Feb 1.
Published in final edited form as: J Immunol. 2009 Dec 28;184(3):1143–1147. doi: 10.4049/jimmunol.0902447

Basophils are transiently recruited into the draining lymph nodes during helminth infection via IL-3 but infection-induced Th2 immunity can develop without basophil lymph node recruitment or IL-31

Sohee Kim *, Melanie Prout **, Hayley Ramshaw †, Angel F Lopez †, Graham LeGros **, Booki Min *,2
PMCID: PMC2849628  NIHMSID: NIHMS180322  PMID: 20038645

Abstract

Basophils are recognized as immune modulators through their ability to produce IL-4, a key cytokine required for Th2 immunity. It has also recently been reported that basophils are transiently recruited into the draining LN after allergen immunization and that the recruited basophils promote the differentiation of naïve CD4 T cells into Th2 effector cells. Using IL-3-/- and IL-3Rβ-/- mice, we report here that the IL-3/IL-3R system is absolutely required to recruit circulating basophils into the draining LN following helminth infection. Unexpectedly, the absence of IL-3 or of basophil LN recruitment played little role in helminth-induced Th2 immune responses. Moreover, basophil depletion in infected mice did not diminish the development of IL-4-producing CD4 T cells. Taken together, our results reveal a previously unknown role of IL-3 in recruiting basophils to the LN and demonstrate that basophils are not necessarily associated with the development of Th2 immunity during parasite infection.

Keywords: basophils, CD4 T cells, IL-3, parasites, Th2 immunity

Introduction

Basophils, the least abundant granulocytes found in the circulation, have recently been proposed to be the most important ‘innate’ source of IL-4 needed for the development of Th2 immunity (1). Such functions are primarily mediated by soluble factors (1-5), which are spontaneously expressed and readily released following activation, and by possible APC functions by which basophils present peptide Ag to naïve T cells (6-8). However, in order for the regulatory roles to be effective, basophils need to be located in close proximity to the Ag activated T cells in vivo. In support of this notion, it was demonstrated that following allergen immunization circulating basophils transiently enter the T cell zone of the draining LN, promoting Th2 differentiation (5). Therefore, basophil entry into the LN seems a critical step for the immune regulation by basophils to occur. However, what recruits circulating basophils into the draining LN during immune responses remains unclear.

IL-3 has previously been demonstrated to play a key role in basophil development and maturation (9). In support of this, it was recently demonstrated that IL-3 induces basophil expansion by promoting granulocyte-monocyte progenitors and basophil/mast cell progenitors to differentiate into basophil lineage progenitors (10, 11). We previously reported that activated T cells are the major source of IL-3 which acts to enhance basophil generation in the bone marrow (BM) during parasite infection (12). Indeed, both basophil generation in the BM and basophil accumulation in the peripheral tissues are significantly impaired in mice deficient in IL-3 (12). However, the maintenance of basal basophil levels is not defective in IL-3-/- mice (9), suggesting that IL-3 action on basophil generation is confined to immune responses.

In this study, we report that IL-3 plays an additional key role in recruiting circulating basophils into the lymphoid tissues. Similar to allergen immunization, circulating basophils were transiently recruited into the draining LN following parasite infection, and the recruitment was completely abolished in the absence of IL-3 or of IL-3 receptor (IL-3R). Paradoxically, wild type level Th2 immunity still developed in parasite infected IL-3-/- mice, suggesting that infection induced Th2 immune responses are independent of IL-3 and of basophil LN recruitment. In support of this, basophil depletion did not abolish infection-induced development of Th2 CD4 T cells. These results suggest that basophil LN recruitment is not necessarily linked to Th2 immunity, suggesting that multiple mechanisms exist for fostering type 2 immune responses in vivo.

Materials and Methods

Mice

BALB/c and BALB/c Rag2-/- mice were purchased from the Jackson Laboratory (Bar Harbor, ME). BALB/c IL-3-/- (9) were provided from Dr. Chris Lantz (James Madison University). IL-3Rβ-/- mice, deficient in both βc and βIL-3 on a BALB/c background, were generated, screened, and bred as described (13) and maintained in the animal facility of the Lerner Research Institute. G4 knock-in mice expressing GFP under the IL-4 promoter were previously described (14). All experimental procedures were conducted according to the guidelines of the Institutional Animal Care and Use Committee.

Parasite infection

Mice were subcutaneously infected with 500 L3 Nippostrongylus brasiliensis larvae as previously reported (15). Basophil recruitment and T cell cytokine production were examined as described below. In indicated experiments, 40μg MAR-1 or hamster IgG was i.v. injected into mice (prior to infection and day 4 after infection).

Flow cytometry

LN and liver cells were examined for basophils. Liver cells were prepared from animals perfused with PBS as previously described (15). In brief, cells were stained with anti-FcγR (clone 93) and anti-CD45 (30-F11). In some experiments, basophils were identified as FcεRIα/CD49b-expressing cells using anti-FcεRIα (MAR1) and anti-CD49b (HMa2). To measure T cell cytokine production harvested cells were stimulated with 10ng/ml PMA plus 1μM ionomycin (purchased from Calbiochem, San Diego, CA) for 4 hours. 2μM monensin (Calbiochem) was added to the culture during the last 2 hours of culture. Cells were harvested and immediately fixed in 4% paraformaldehyde. Fixed cells were subsequently permeabilized in PBS-0.1% saponin/0.1% BSA buffer, and incubated with anti-CD4 (RM4-5), anti-IL-3 (MP2-8F8), anti-IL-4 (11B11), and anti-IL-13 (eBio13A). All antibodies were purchased from eBioscience (San Diego, CA). Samples were acquired using a FACSCalibur (Becton Dickinson, Franklin Lakes, NJ) and analyzed using FlowJo (Treestar, Ashland, OR).

BM reconstitution

BM cells collected from tibia and femur of the donor animals were transferred i.v. into the lethally irradiated (1100 rad) recipients (~10× 106 cells per recipient). 1 mg of gentamycin was injected i.p. into the recipients at day 0 and day 2 of BM transfer. Prior to experiments, successful BM cell reconstitution was confirmed by FACS analysis. Typically, reconstituted mice were used between 6-8 weeks after BM transfer.

Data analysis

Statistical significance was determined by the Student's t-test using the Prism (GraphPad Software, La Jolla, CA). p<0.05 was considered to indicate a significant difference.

Results and Discussion

IL-3-dependent basophil LN recruitment following parasite infection

Infection with intestinal nematode Nippostrongylus brasiliensis (Nb) induces robust type 2 immune responses (16), although mechanism(s) underlying Nb induced Th2 immunity remain elusive. The infection also enhances basophil generation in the bone marrow and subsequent accumulation in the peripheral tissues, including liver, lung, and spleen (15, 17). It was recently reported that circulating basophils are transiently recruited into the draining LN after subcutaneous allergen immunization and that these recruited basophils play key roles in the development of allergen specific type 2 immune responses by primarily producing IL-4 (5). We therefore examined whether such basophil recruitment occurs during Nb infection and, if so, acts to promote Nb induced Th2 immunity in vivo. Our initial attempts to detect basophil accumulation in the draining LN failed when measured at the peak of the responses (15); however, in this study we examined if basophil accumulation occurs early during infection as seen during allergen immunization (5, 8). Draining mediastinal LN (medLN) were examined for the presence of basophils 3, 4 and 10 days after infection. Basophils were identified as FcγRhighCD45int cells as previously reported (1, 2). As seen in allergen and Schistosoma egg-induced immune responses (5, 8), basophils were indeed recruited into the medLN 3 and 4 days post infection (222 ± 108 basophils in naïve animals and 3738 ± 1796 basophils in Nb infected animals at day 4 post infection, Fig 1A). The recruitment was transient, thus almost no basophils remained in the medLN 10 days post infection (Fig 1A). Interestingly, basophils were also recruited into the mesenteric LN (mLN) later during infection, i.e., 10 days post infection (Fig 1A). Because the medLN and mLN are the major sites of immune responses during early and late infection, respectively (18), these results suggest that the major Ag draining LN are the key sites for basophil recruitment.

Fig 1. Basophil LN recruitment requires IL-3.

Fig 1

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(A) Groups (n=4) of wild type and IL-3-/- mice were infected with Nb, and sacrificed 3, 4, and 10 days post infection. Mediastinal (Med LN) and mesenteric (mLN) LN were examined for basophils (FcγRhigh CD45intermediate) by FACS. Data shown represents the mean ± SD of individually tested mice. (B) Wild type and IL-3-/- CD4 T cells were transferred (5 × 106 per recipient) into Rag2-/- mice. The recipients were infected with Nb 14 days after the transfer. Basophil mLN recruitment was determined by FACS analysis 10 days post infection. Each symbol represents individual mouse.

We recently reported that the IL-3 produced by activated CD4 T cells plays a key role in inducing basophil generation in the bone marrow and the subsequent accumulation in the peripheral tissues (12). To test if IL-3 also plays a role in basophil LN recruitment, groups of wild type and IL-3-/- mice were infected with Nb, and the medLN was examined for the presence of recruited basophils. To our surprise, basophils failed to enter the medLN in the absence of IL-3 (Fig 1A). Similarly, recruitment of basophils to the mLN at 10 days post infection was also abolished in Nb infected IL-3-/- mice (Fig 1A). Because IL-3 is mainly produced by activated T cells (12), this result suggests that basophil LN recruitment requires IL-3 produced by CD4 T cells (17). Indeed, basophil mLN recruitment was observed in mLN of Nb infected Rag-/- mice that received wild type CD4 T cells but not in those mice that received IL-3-/- CD4 T cells (Fig 1B). Notably, infection induced basophil generation in the BM only becomes detectable after 7 days of infection (12), thus basophils recruited into the medLN are likely from the preexisting pools in the circulation. Because the basal maintenance of basophils without infection is independent of IL-3 (9), the lack of basophil recruitment in IL-3-/- mice is not due to defects in infection- or IL-3-mediated basophil generation. Taken together, these results suggest that basophils are recruited into Ag draining lymphoid tissues and that the recruitment appears to be dependent on T cell activation and IL-3 production.

Dependence on IL-3R for basophil recruitment

The question of how IL-3 mediates basophil recruitment to the LN is unclear. It was previously reported that IL-3 can induce chemokine and adhesion molecule expression on endothelial cells, enhancing transendothelial migration of human basophils in vitro (19, 20). To directly examine the IL-3 target cells involved in basophil recruitment we generated BM chimeras using IL-3Rβ-/- mice deficient in both IL-3Rβc and IL-3RβIL-3 (13). Wild type BM cells were transferred into lethally irradiated IL-3Rβ-/- recipients, in which only recipient-derived cells including endothelial cells are IL-3Rβ-/-. Alternatively, IL-3Rβ-/- BM cells were transferred into lethally irradiated wild type recipients, where BM derived cells are deficient in IL-3Rβ but endothelial cells express the receptor. Successful reconstitution was confirmed by measuring IL-3Rβc (CD131) expression of blood cells (data not shown). Groups of reconstituted mice were infected with Nb and basophil recruitment into the medLN was examined 4 days after infection (Fig 2A). Basophil recruitment was found in Nb infected WT BM -> IL-3Rβ-/- but not in IL-3Rβ BM -> WT group, strongly suggesting that IL-3Rβ expression on the BM derived cells is necessary for the recruitment (Fig 2A) and that the IL-3 target cells are of BM origin. Of note, basophil levels in the blood of these BM chimeras were similar prior to infection, thus the lack of basophil recruitment to the LN is not a defect of basophil development (Fig 2B). Nb infection-induced basophil accumulation in the liver occurred in WT BM -> IL-3Rβ-/- mice compared to uninfected mice; however, the accumulation was only marginally induced in IL-3Rβ-/- BM -> WT recipients (Fig 2C). WT BM -> WT recipients showed substantial basophil accumulation in the liver, while such accumulation was not found in IL-3Rβ-/- BM -> IL-3Rβ-/- mice (Supplementary Fig 1). These data strongly suggest that the IL-3 target cells involved in basophil LN recruitment are not endothelial cells in vivo.

Fig 2. IL-3 acts on BM derived cells to mediate basophil recruitment.

Fig 2

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Wild type and IL-3Rβ-/- BM cells were transferred into lethally irradiated IL-3Rβ-/- and wild type recipients, respectively. Reconstitution was confirmed by measuring IL-3Rβ expression. (A) Mice were infected with Nb, and medLN was examined for basophils at 4 days post infection. (B) Blood basophil levels of reconstituted mice were determined prior to Nb infection. (C) Mice were infected with Nb, and liver basophils were examined 10 days after infection. Uninfected control mice are shown as controls. Each symbol represents an individual mouse.

IL-3-/- but not IL-3Rβ-/- mice develop Nb specific Th2 immunity

The finding that in the absence of either IL-3 or of IL-3Rβ basophils fail to be recruited to the draining LN prompted us to test whether recruited basophils contribute to the T cell immunity in vivo. T cell differentiation was examined in Nb infected wild type, IL-3-/-, and IL-3Rβ-/- mice. We found that IL-3-/- mice mounted wild type level Th2 responses; CD4 T cells from the medLN and the liver of Nb infected IL-3-/- mice expressed comparable levels of IL-4 and IL-13 (Fig 3A, 3B, 3D, and 3E). In addition, no difference was found in CD4 T cell cytokine production between wild type and IL-3-/- mice when measured on 4 days after infection (Supplementary Fig 2). By contrast, CD4 T cells from Nb infected IL-3Rβ-/- mice failed to develop Th2 type T cell responses. The failure of IL-3Rβ-/- mice to mount Th2 immunity could be partly due to defective T cell activation, because of defective IL-3 production in IL-3Rβ-/- CD4 T cells (Fig 3C and 3F). Indeed, the frequency of activated phenotype (CD44hiCD62Llo) CD4 T cells in Nb infected IL-3Rβ-/- mice was lower than that in wild type mice (15.5 ± 1.1 for IL-3Rβ-/- and 30.5 ± 3.8 for WT mice). The frequency of activated phenotype CD4 T cells in naïve mice was slightly higher in WT (~14%) than in IL-3Rβ-/- (~9%) mice (data not shown). Of note, the development of Th1 phenotype CD4 T cells is relatively minor during Nb infection, thus no major differences in IFNγ+ CD4 T cells in Nb infected wild type and IL-3Rβ-/- mice were noticed (Supplementary Fig 3). The exact reason for a defective Th2 response in IL-3Rβ-/- mice remains to be examined. T cells may require IL-5 or GM-CSF to become Th2 cells, or alternatively these mice are biased to respond inappropriately. Indeed, it was recently reported that the cells from these mice exhibit defects in activation as well as recruitment to sites of challenge (13), which may be a direct consequence of being unable to recognize GM-CSF, IL-5, or IL-3, or an effect secondary to limited numbers of dendritic cells well known to require GM-CSF or IL-3 for their full development and function. Serum IgE concentration measured at the peak of the responses was found similar to T cell responses: 915 ± 62μg/ml in wild type mice, 675 ± 216μg/ml in IL-3-/- mice, and 104 ± 12μg/ml in IL-3Rβ-/- mice.

Fig 3. Nb infection induced Th2 responses are unaffected in IL-3-/- mice.

Fig 3

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Groups of wild type, IL-3-/-, and IL-3Rβ-/- mice were infected with Nb, and sacrificed 10 days post infection. Mediastinal LN (A, B, C) and Liver (D, E, F) cells were stimulated with PMA plus ionomycin, and CD4 T cell cytokine production: IL-4 (A and D), IL-13 (B and E), and IL-3 (C and F) was determined by FACS analysis. *, p<0.05; **, p<0.01, ***, p<0.001, ns, not significant. Each symbol represents an individual mouse.

To confirm that basophils are dispensable for Nb-induced Th2 immunity, we injected GFP/IL-4 (G4) knockin mice (14) with basophil depleting Ab, MAR-1 into Nb infected mice and examined the development of GFP (IL-4)-expressing CD4 T cells. As shown in Fig 4, MAR-1 Ab injection efficiently depleted basophils in the mLN. Yet, CD4 T cell IL-4 production (GFP expression) was not reduced by the absence of basophils (Fig 4), further supporting that basophils are dispensable for the development of Th2 immunity following Nb infection.

Fig 4. Basophil-independent Th2 differentiation in Nb infected mice.

Fig 4

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Groups of G4 mice received i.v. 40μg MAR-1 or control Ab prior to infection. Following Nb infection, mice were treated with Ab on day 4 post infection. The basophil levels in mLN as well as GFP expression of splenic and mLN CD4 T cells were determined 10 days post infection. Each symbol represents individual mouse.

The mechanisms underlying the development of in vivo Th2 immune responses remain unclear. IL-4 has been considered the master regulator that promotes Th2 differentiation via activation of STAT6 and GATA3 (21), although there have been several reports showing that Th2 immunity can develop independently of IL-4 under certain circumstances (22, 23). Our study from IL-3-/- mice further provides evidence that basophils are dispensable during Nb induced Th2 immunity. This finding is consistent with previous studies showing that non-CD4 T cell derived IL-4 is not necessary for Th2 differentiation in vivo (5, 22, 24, 25). As recently been reported, the nature of Ag may determine the mechanism of Th2 immune responses (26). For example, parasite associated Ag may bypass the requirement for IL-4, and further of basophils to generate in vivo Th2 immune responses. Further investigation will be necessary to examine this possibility.

In vitro, stimulation of endothelial cells with IL-3 has been demonstrated to induce selective transmigration of human basophils (20, 27, 28). However, our data shows that in vivo the cellular target of IL-3 is of BM origin. Further investigations will be required to identify these targets. Chemokines including CCL11 and CCL2 were shown to mediate basophil migration (20, 29). Adhesion molecules such as β2 integrin, P-selectin, as well as CD49d have been demonstrated to induce basophil rolling and adhesion (27, 28). Whether these mechanisms operate during IL-3-dependent basophil recruitment to the LN will be an important area of investigation.

The roles of IL-3 in basophil biology seem to be manifold (9, 10, 12, 30) and, now include the recruitment of basophils into the draining LN. Given that IL-3 is mainly produced by activated T cells, these results imply the requirement of adaptive immunity for the basophil responses to develop (12, 17). Unraveling the cellular mechanisms will prove useful to develop therapeutic approaches to inhibit basophil recruitment into effector sites. Moreover, our data also demonstrate that Th2 immune responses may develop in a basophil-independent manner and that cautious analysis of each Th2 immune response will be necessary.

Footnotes

1

Supported by the startup funds from the Cleveland Clinic Foundation and by the NIH grant AI080908 (to B.M.)

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