Although we have known for decades that B cells contribute to immune responses by secreting Ab, it is now clear that they are more than simply factories for Ig production, and they also play key roles as modulators of T cell–dependent immunity. Indeed, the evidence showing that Ag-presenting and cytokine-producing B cells can alter the magnitude and quality of CD4 T cell responses continues to grow. In this article, we review the data showing that B cells, working in partnership with dendritic cells, regulate the development of Th2 cells and the subsequent allergic response.

In 1986, Mosmann et al. (1) identified two CD4 T cell subsets, referred to as Th1 and Th2 cells, which express unique patterns of cytokines following restimulation. Subsequent work from many laboratories demonstrated that the development of these two CD4 T cell populations is reliant on different transcriptional programs and that the CD4 effectors play distinct roles during immune responses (2). For example, the IFN-γ–producing Th1 cells are thought to be critical for elimination of intracellular pathogens, whereas the IL-4–producing Th2 cells are believed to regulate immune responses to multicellular organisms like nematodes. Collectively, these findings established the backbone of the Th cell–differentiation hypothesis (3) and paved the way for the subsequent identification of additional Th subsets, including the IL-17–producing Th17 cells, the IL-10–producing regulatory T cells (Tregs), and the IL-21–producing T follicular helper (TFH) cells (4). Each of these T cell subsets exhibits different functional properties, and the development of each lineage is programmed by a distinct transcription factor (4). Although we know much about the molecular cues that initiate development of Th1 cells, Tregs, and Th17 cells (4), our understanding of the signals that initiate the Th2-developmental pathway are less clear, despite almost three decades of intense study. In this review, we discuss how dendritic cells (DCs) and B cells, working in concert, can initiate and sustain Th2 development.

Effective priming of naive CD4 T cells is dependent on “professional” APCs that express costimulatory molecules and present Ag-derived peptides complexed with MHC class II (MHCII) (5). DCs are thought to be the key professional APCs and are critical for T cell priming because transient depletion of DCs in vivo impairs naive CD4 T cell priming in most experimental settings (6). Not surprisingly, given the important role of DCs in CD4 T cell priming, DCs are also thought to provide signals that are critical for expression of the transcriptional factors that control the differentiation of the primed CD4 T cells into the different effector populations (7). For example, IL-12–producing mature DCs induce expression of the Th1 lineage–specifying transcription factor, T-bet, in the primed CD4 T cells, and this DC-dependent signal is required to induce full Th1 development (8). Likewise, it is reported that DCs are necessary to induce Th2 development (9, 10) and are also sufficient for Th2 differentiation, because adoptive transfer of DCs, isolated from the lymph nodes (LNs) of animals exposed to house dust mite (HDM) allergen, into the lungs of naive mice is sufficient to induce a Th2 response in the mice following aerosol challenge with HDM (11). However, the paradigm that DCs are the only APC involved in Th2 development has been challenged with recent data showing that Ag presentation solely by DCs may not induce optimal Th2 development. For example, basophils, which express MHCII molecules and can produce the Th2 lineage inducing cytokine, IL-4, are reported to be sufficient to induce Th2 development (12). Although these findings are controversial, additional studies looking at mice in which DCs are the only cell type able to present peptide–MHCII complexes to T cells in vivo showed that Th2 development is impaired following exposure to pathogens like Trichuris muris (13) or allergens like papain (14). Thus, the data suggest that additional APCs likely provide signals that facilitate the generation, expansion, or maintenance of Th2 cells.

B cells, just like DCs, express MHCII and, when appropriately activated by Ag, cytokines, and/or pathogen-derived TLR ligands, also upregulate costimulatory molecules and can present Ag to naive CD4 T cells (15). Although initial studies looking at allergic responses in the genetically B cell–deficient μMT mouse strain suggested that B cells play no role in the development of the Th2 response (16, 17), later studies using additional pathogens and allergens revealed that B cells can, in some settings, modulate Th2 development. For example, Th2 development in response to infection with the helminth Heligmosomoides polygyrus is impaired in B cell–deficient μMT mice and in transiently B cell–depleted mice (1820). Similarly, Th2 cytokines in the lung airways and tissue are significantly lower in μMT mice exposed to HDM, and the HDM-exposed B cell–deficient mice exhibit decreased airway hyperresponsiveness after methacholine challenge (21). Following an erythrocytic infection with Plasmodium chabaudi chabaudi, C57BL/6 mice develop a Th1 response that switches to a Th2-dominant response later in the primary response (22). In contrast, B cell–deficient μMT mice continue to retain a Th1-like response to the malarial Ags throughout the primary infection, resulting in a chronic relapsing parasitemia (22). In other experimental settings, B cell deficiency is associated with immune deviation away from a Th2-polarized response toward a Th1-dominant response. For example, following exposure to Schistosoma mansoni eggs (23) or infection with T. muris (24), T cells from B cell–deficient mice make an IFN-γ–dominant response. Likewise, following infection with Leishmania major LV39, CD4 T cells from normal BALB/c mice make IL-4 and IFN-γ following restimulation, whereas CD4 T cells from B cell–deficient BALB/c mice produce only IFN-γ, rendering this normally susceptible strain of mice resistant to L. major (25). Taken together, the data demonstrate that B cells can influence the development and/or maintenance of the Th2 response.

Given the ability of B cells to specifically capture Ag bound to the BCR, one obvious way in which B cells might modulate CD4 T cell responses is by presenting Ag and providing costimulation to CD4 T cells (15). Although studies examining mice in which only the B cells are competent to present Ag indicated that B cells have only a limited ability to initiate CD4 T cell responses following i.v. or s.c. vaccination (26), it is clear that the development and maintenance of the TFH lineage are highly dependent on B cells, as well as on Ag-presenting, ICOS-L–expressing B cells that present Ag and provide costimulation (27, 28). Given the recent reports suggesting that Th2 cells and an IL-4–competent TFH subset may arise from a common precursor (29), some of the earlier studies showing alterations in the development of IL-4–producing T cells in B cell–deficient mice may be attributable, at least in part, to an inability of these mice to sustain the IL-4–producing TFH cells (TFH2). However, recent studies from our laboratory (18), using transient B cell depletion in the H. polygyrus infection model to study the IL-4–producing TFH2 and IL-4 + IL-13–producing Th2 cells in the LN and peripheral sites, clearly demonstrate that B cells regulate the maintenance or expansion of both IL-4–producing cell lineages. It is tempting to speculate that B cells, in concert with DCs, regulate the development of the putative IL-4–competent TFH/Th2 precursor and that sustained interactions between B cells and this precursor reinforce the TFH developmental program, whereas transient and nonsustained interactions between B cells and the TFH/Th2 precursor favor commitment to the Th2 lineage. Nevertheless, it is clear that any reported roles for B cells in sustaining or expanding different CD4 effector populations—be they Th1, Th2, Th17, or Treg—will need to be carefully assessed to ensure that the changes observed are not due to the loss of B cell–dependent TFH cells that retain the ability to produce effector cytokines like IFN-γ, IL-17, and IL-4.

The data from our laboratory and others (1823), showing that Ag-specific B cells regulate the development of the TFH and Th2 response in the LN and the magnitude of the Th2 response at effector sites, suggest that B cells are likely presenting Ag to the T cells. In support of this hypothesis, multiple publications report that CD4 Th2 effector responses are diminished in mice that are selectively unable to express MHCII in B-lineage cells (B-MHCII−/− mice). For example, CD4 T cell expansion is reduced and IL-4 production by the restimulated T cells is greatly decreased in B-MHCII−/− mice following immunization with protein Ags in alum (30) and after repeated exposures to cockroach Ags (21). Likewise, Th2 primary and memory responses are significantly impaired in H. polygyrus–infected B-MHCII−/− animals (20). Interestingly, although Ag presentation by B cells is required for the development of both primary and memory Th2 responses following vaccination or infection, Th1 differentiation is reportedly normal in B-MHCII−/− mice (30), suggesting that B cells provide unique costimulatory signals that specifically promote or sustain Th2 development.

Several studies support the concept that particular costimulatory pathways enhance Th2 development. Indeed, experiments using CD28-deficient mice reveal that Th2 responses to some pathogens and allergens are impaired in the absence of CD28 signaling (31). Interestingly, these mice are competent to initiate normal Th1 responses to other Ags (31), suggesting that Th2 development is more dependent than Th1 development on engagement of CD28 by costimulatory CD80/CD86 ligands. Likewise, signaling through OX40 seems to be critical for Th2 differentiation in various experimental models (3234), and studies with ICOS-deficient mice and ICOS/ICOS-L blockade reveal a role for this T cell costimulatory pathway in Th2 differentiation (35). It is reported that OX40L expression by B cells is required for the development of a primary effector and memory Th2 response following vaccination with protein Ags in alum (36). Likewise, expression of both CD80 and CD86 by the B cells is required for the development of the primary Th2 response to H. polygyrus (19). Although the experiment to assess the role of ICOS-L–expressing B cells in Th2 development has not been performed, prior studies showed that ICOS-L expression by B cells is critical for TFH development and maintenance (28). Given the role for B cell–derived costimulation during the development of both TFH and Th2 cells, it is again tempting to speculate that B cells may provide costimulatory signals that promote the development of a common TFH2/Th2 precursor. Regardless, the collective data suggest a role for B cell–mediated costimulation during the development of Th2 responses.

Th2 development is influenced by the type of costimulation provided to the naive T cells by the APC, as well as by the strength of the TCR signal received by the T cell. Indeed, the combination of peptide/Ag dose and costimulation provided by the APC affects the balance between Th1 and Th2 development, with low TCR signal–strength interactions promoting Th2 development (37). For example, in vitro priming of naive CD4+ T cells with low concentrations of MHCII–peptide complexes (38, 39) or low-affinity MHCII–peptide complexes (40) preferentially induces Th2 differentiation. Likewise, low-affinity or low-avidity TCR stimulation promotes IL-4–independent expression of the Th2 master regulator transcription factor, GATA-3 (41). In contrast, stimulation with high concentrations of peptide abrogates early GATA-3 expression and prevents Th2 development (41). In agreement with the “low TCR-strength model,” T2 RNase/omega-1, a glycoprotein derived from S. mansoni egg with Th2 adjuvant-like properties, can condition DCs to drive Th2 polarization by altering the ability of the DC to form stable conjugates with the T cell (42). This Ag-directed weak conjugate formation is presumed to decrease the TCR signal that the naive CD4+ T cell can receive and, thereby, facilitate Th2 development. Likewise, it is thought that low expression of Ag–MHCII complexes on the surface of an APC also may decrease the stability of the DC/T cell conjugates (43), resulting in weaker TCR stimulation and favoring Th2 development. Supporting this concept, basophils, which express low levels of MHCII molecules, can act as APCs for CD4+ T cells; however, these cells preferentially prime Th2 responses when tested in vitro and in vivo (12).

B cells, like basophils, may preferentially induce weak TCR stimulation. However, in the case of B cells, this is not due to constitutively low MHCII expression but rather to the unique ability of B cells to present Ag late in the immune response when Ag levels are declining (44, 45). B cells, unlike DCs or basophils, collect Ag in a specific fashion through binding of the Ag to the BCR (44). As the levels of soluble Ag decline following pathogen clearance, B cells become more efficient than DCs at capturing and presenting Ag to CD4 T cells (46). It is proposed that T cell priming occurs through sequential stable interactions between the responding T cells and different APCs (47). In a sequential model of T cell priming, DCs may initiate T cell priming and clonal expansion when Ag is present in excess, whereas B cells may play a more important role in sustaining the CD4 T cell–differentiation program when Ag becomes limiting. This model appears to describe TFH development, which is known to be dependent initially on Ag-presenting DCs for the first priming and lineage-commitment steps and later on Ag-presenting B cells to complete the developmental process and sustain the lineage (27, 28). Given that B cells may be the predominant APC in LNs for new cohorts of T cells late in the primary response when Ag is limiting, it is likely that the number of MCHII–peptide complexes presented by the B cells to the T cells will be decreased relative to earlier in the response and that these new cohorts of Ag-specific T cells will receive a weaker TCR signal from the B cells. Strikingly, some pathogens, like malaria, induce an initial Th1 response that spontaneously switches to a Th2 response later during the primary response (22). This switch from the Th1-dominant response to a Th2-driven response fails to occur in B cell–deficient mice (22). However, this switch from Th1 to Th2 development clearly does not occur in all infection models, even as Ag becomes limiting, so there must be other signals beyond Ag availability that dictate Th2 development in response to malaria infection. Regardless, the data suggest that establishment of late cognate interactions between B cells and CD4 T cells may facilitate the full commitment of T cells to the Th2 program, both through the unique costimulatory signals provided by the B cells and through the selective low TCR signal–strength interactions that take place late in the response.

According to the current paradigm (7), pathogen-associated molecular patterns (PAMPs), expressed by the pathogens, can activate pathogen-associated molecular pattern recognition receptors (PRRs), expressed by DCs. This interaction causes the upregulation of MHCII and costimulatory molecules on the DCs and induces the DCs to secrete the Th1-polarizing cytokine, IL-12. Naive CD4 T cells, activated in the presence of IL-12 or IFN-γ, upregulate T-bet, and T-bet directs the responding T cells to differentiate into Th1-lineage cells and secrete Th1 cytokines like IFN-γ (8). IL-12 can induce the differentiation of TFH cells with the ability to produce IFN-γ [TFH1 cells (4851)]. Interestingly, B cells also can produce IL-12 and IFN-γ and, under some conditions, they are important for the expansion or maintenance of the Th1 response (52, 53). Given the important role for both DCs and B cells in the development and maintenance of TFH cells, it is possible that B cells and DCs cooperate to induce optimal TFH1 and Th1 responses.

A similar cytokine-dependent model (37) was originally proposed for Th2 development, whereby the lineage-driving cytokine, IL-4, produced by the APC in response to pathogen-directed signals induces upregulation of the Th2 lineage–specifying transcription factor GATA-3 in the T cell. However, the in vivo evidence to support the model that DCs are conditioned by pathogen signals to differentiate into a DC that produces Th2-polarizing cytokines (DC-2 cell) is limited (54). First, no specific PRRs, PAMPs, or damage-associated molecular patterns (DAMPs) are known to initiate IL-4 production by DCs (54). Second, there is no compelling evidence to support the supposition that DCs must be the initial source of IL-4 for the T cells (37, 54), and it is now proposed that other cell types, including the newly identified type 2 innate lymphoid cells (55), basophils (12), or the conventional T cells themselves (37), may serve as the initial source of IL-4. Finally, IL-4R– or STAT6-deficient CD4 T cells can develop into Th2 cells in some settings (37), indicating that IL-4 signals are not obligate for Th2 commitment. Indeed, these in vivo results are in agreement with the in vitro studies showing that weak TCR signals in the absence of IL-4 are sufficient to initiate Th2 development (39, 41). Thus, although IL-4 may be critical for expansion and maintenance of the Th2 response, early Th2 development to some pathogens and Ags may, in fact, occur independently of IL-4 signals provided by the APC.

If DCs are not instructed by the pathogen to make IL-4, how do DCs initiate Th2 induction and how might B cells provide Th2-conditioning signals to the DCs? Several studies suggested that Th2 development may occur as a default pathway when Th1-polarizing cytokines or PAMPs/DAMPs that can activate PRRs expressed by the DCs are lacking (56). Based on this model, Th2 differentiation occurs whenever DCs are activated in the absence of IL-12–inducing pathogen-derived adjuvants. Conversely, the model predicts that the presence of IL-12 at the site of contact between the T cells and Ag-presenting DCs will inhibit Th2 development, even when the pathogen or Ag would normally promote the development of a Th2 response. B cells can secrete many cytokines (53), including IL-12 and IFN-γ (52), both of which promote T-bet expression in T cells and Th1 differentiation (8), as well as IL-10 (57), which can suppress IL-12 production by DCs (58). Multiple studies suggest that B cells may be able to regulate the DC-mediated priming of Th2 responses by modulating the cytokine microenvironment. As one example, B cell–deficient mice are reported to make IFN-γ, and not IL-4, following infection with the nematode T. muris (24). However, treatment of the infected μMT mice with blocking anti–IL-12 Abs is sufficient to restore the normal Th2 response in B cell–deficient animals (24), suggesting that B cells may tune the Th2-priming capacity of DCs by creating a Th2-permissive microenvironment. In support of this hypothesis, another study showed that adoptively transferred keyhole limpet hemocyanin–pulsed DCs from B cell–deficient μMT mice are unable to induce the development of IL-4–producing CD4 effectors (59). This study further shows that DCs obtained from B cell–deficient μMT mice secrete more IL-12 p40 compared with DCs obtained from control animals (59). The increased production of IL-12 by DCs from B deficient–mice appears to be due to the loss of IL-10–producing B cells, because treatment of μMT DCs with IL-10 restores the IL-4–priming capacity of DCs (59). Interestingly, mice containing B cells that are selectively deficient in IL-10 (60) or IL-2 (20) also show impaired Th2 responses. It is still unknown whether cytokines produced by B cells control T cell polarization through direct signaling in the T cells, as might by the case for IL-2 (61), or by preventing the DCs from making IL-12, as might be the case for IL-10 (59, 62). However, it is clear that the loss of Th2 immunity observed in B cell–deficient mice is not always associated with immune deviation toward a Th1 response. In fact, although B cell–deficient mice show impaired Th2 responses postinfection with H. polygyrus (1820), exposure to allergens (21), or vaccination with Ags adsorbed in alum (30, 36), Th1 responses are not enhanced in these settings. These data suggest that B cells may be able to influence the capacity of DCs to prime Th2 responses by mechanisms other than simply preventing their production of Th1-polarizing cytokines.

Encounters between naive CD4 T cells and Ag-bearing APCs are regulated by a finely tuned balance between expression of homeostatic chemokines by stromal cells in the LN and chemokine receptors expressed by T cells and APCs (63). According to the accepted model (64), CCR7-expressing naive T cells enter the T cell area of the LN through high endothelial venules and are retained within this region of the LN by the ligands for CCR7, CCL19, and CCL21, which are produced by the stromal-derived fibroblastic reticular cells. DCs upregulate CCR7 in response to PRR activation and migrate in a CCR7-dependent fashion through the lymphatics to the LN (65). Upon entering the LN through the subcapsular sinus, the CCR7+ DCs migrate through the cortical sinuses past the B cell follicles to the CCL19/CCL21-expressing T cell zone of the LN, where the DCs encounter T cells, present Ag, and initiate T cell priming and differentiation (65). CXCR5-expressing B cells localize to the B cell follicles in close proximity to the stromal-derived follicular dendritic cells that produce the CXCR5 ligand, CXCL13 (66). Thus, the B cells are most likely to encounter T cells during the initial migration of the B cells from high endothelial venules to B cell follicles, at the borders between the T cell zone and B cell follicle (T/B border), or between B cell follicles in the interfollicular region (66). As might be expected, disrupting T cell/DC colocalization within the LN can affect T cell priming. In fact, primary T cell responses to several experimental Ags and pathogens are impaired in CCR7-deficient mice (63). However, plt/plt mice, which lack the CCR7 ligands, CCL19 and CCL21a, can make normal or even exacerbated Th2 responses (18, 67), suggesting that Th2 differentiation may not need to take place within the T cell area of the LN and/or that the APC that initiates a Th2 response may not need to express CCR7 at the time of priming. Interestingly, multiple studies showed that Th2 cells preferentially accumulate at the interface of the T/B cell border (19, 68), whereas Th1 cells are found primarily within the T cell area (68, 69). The preferential localization of Th2 cells in close proximity to B cells suggests that unique signals or cells that facilitate the development of Th2 responses might be present in this specialized interfollicular microenvironment. This view is supported by the observation that initial priming of Th2 responses following Nippostrongylus brasiliensis infection occurs at the border of the B cell follicle and T cell zone and not in the T cell area (19). Recent work from our laboratory using the H. polygyrus infection system further supports the model that Th2 differentiation requires the close interactions between CD4 T cells and B cells. In fact, we find that CXCR5 is rapidly upregulated on pathogen-responsive CD4 T cells following H. polygyrus infection and that these T cells accumulate in the interfollicular areas and T/B cell border (18). The altered localization profile of the CD4 T cells is controlled by Ag-activated B cells (18) that produce lymphotoxin-α (LT), a cytokine that induces expression of the CXCR5 ligand, CXCL13, by the follicular dendritic cells via a positive-feedback loop (70). Thus, in the absence of Ag-specific B cells or B cell–derived LT, activated CD4 T cells fail to localize to the interfollicular region or T/B cell border of the LN, and Th2 development is significantly impaired.

Interestingly, the CD4 T cells are not the only cell type to reposition near B cell follicles. In fact, following H. polygyrus infection, the intestinal-derived migratory DCs upregulate expression of CXCR5 and gradually lose expression of CCR7 (18). These DCs are preferentially retained in the subcapsular sinus and interfollicular areas of the LN and appear unable to be recruited to, or retained in, the T cell zone (18). Furthermore, similar to what we observed for CD4 T cells, the positioning of DCs near the B cell follicle is controlled by the LT-expressing B cells, which regulate expression of CXCL13 in the reactive LN (18). More importantly, eliminating CXCR5 expression on either the DCs or the CD4 T cells is sufficient to prevent optimal TFH and Th2 development following H. polygyrus infection (18). Although one can argue that deleting CXCR5 expression in either the DCs or T cells simply prevents the colocalization of these cells, we found that blocking CXCR5 signaling in both cell types resulted in colocalization of the DCs and T cells in the T cell zone, yet Th2 development was still impaired (18). Collectively, these data indicate that following H. polygyrus infection, DCs and CD4 T cells are both instructed, potentially by pathogen-derived Ags, to upregulate CXCR5 and colocalize in close proximity to the CXCL13-expressing stromal cells and B cells. This early encounter between naive CD4 T cells and DCs near the T/B cell border, which is controlled by LT-producing B cells, appears to be an important determinant for Th2 commitment.

One remaining question is why the colocalization of DCs and T cells near the B cell follicles preferentially favors Th2 development. One possibility is that the CXCR5+ DCs do not receive critical signals in the T cell zone that condition the DCs to induce Th1 differentiation and that these DCs induce Th2 differentiation via the “default pathway” described earlier (56). In support of this possibility, engagement of CCR7 on DCs by CCL19 induces upregulation of costimulatory molecules and secretion of IL-12 by the DCs (71), both of which favor the preferential priming of Th1 responses. Thus, CXCR5+ DCs may not receive sustained CCR7-dependent activation signals and are simply unable to produce sufficient IL-12 to drive a Th1 response. Alternatively, we can speculate that a positive signal delivered by CXCL13 alters the activation/maturation program of DCs in a way that facilitates their Th2-priming capacity. Finally, it is possible that the specialized microenvironment in the interfollicular areas and T/B cell border may specifically condition the DCs or T cells in a way that favors Th2 development. We can envision a scenario whereby serial cognate interactions between T cells and DCs and ICOS-L– and OX40-expressing B cells at the T/B cell border might specifically favor Th2 development. Alternatively, interactions between DCs and B cells or between DCs and other cells located in the interfollicular area, including mast cells (37) and marginal reticular cells (72), might condition the Ag-bearing DCs to initiate Th2 development. Although we still do not understand how this specialized microenvironment promotes Th2 induction, the data indicate that one of the major, and completely unexpected, ways in which B cells can regulate Th2 development is by producing a cytokine that is required to orchestrate the CXCL13-dependent encounters between Ag-bearing DCs and T cells in close proximity to Ag-activated and Ag-presenting B cells.

Until recently, the role(s) for B cells in regulating T cell–mediated immunity have not been well appreciated. However, over the last decade it has become increasingly clear that B lineage cells can, in defined infection and autoimmune settings, regulate the development, maintenance, and/or expansion of multiple effector and memory CD4 T cell subsets, including Th1 cells, TFH cells, Tregs (reviewed in Ref. 53), Th17 cells (73) and, as discussed in this article, Th2 cells. In the case of Th2 cell development, the data suggest that B cells can play at least three separate roles (Fig. 1). First, B cells, through their ability to present Ag and provide specific costimulatory signals to T cells, can cooperate with Ag-presenting DCs that do not make IL-12 to initiate and sustain Th2 development. Second, B cells can produce cytokines, like IL-2 and IL-10, which act on T cells or DCs to promote Th2 development and prevent alternate fate decisions. Finally, B cells can ramp up the LT/CXCL13 positive-feedback loop in the LN to facilitate the colocalization of DCs, CD4 T cells, and B cells within the interfollicular region of the LN, a microenvironment that appears to favor Th2 development. Although the experiments supporting a role for B cells in Th2 development have come from animal models, the use of B cell–depletion therapy to treat patients suffering from a number of chronic, supposedly T cell–mediated, inflammatory diseases (74) reveals that human CD4 T cell responses are also regulated by B cells. Although B cell–depletion therapies have not been tested in humans suffering from Th2-mediated inflammatory diseases, patients with X-linked agammaglobulinemia, who have decreased numbers of mature B cells, are reported to exhibit a skewed Th1 profile, with reduced Th2 activity (75). These data and the data from B cell–depleted and B cell–deficient mice strongly suggest that B cells play an important role in modulating Th2 responses. In the future, a better understanding of the mechanism(s) by which B cells influence the development and maintenance of Th2 responses may provide insights into potential B cell–, LT-, or CXCL13-directed therapeutic approaches to treat Th2-mediated inflammatory diseases.

FIGURE 1.

Cooperation between B cells and DCs can facilitate Th2 development in response to nematode infection. The accumulating data suggest that DCs are necessary, but not always sufficient, to initiate the priming of naive CD4 T cells and the initial commitment of the primed T cells to the Th2-developmental pathway. Ag-specific activated B cells can play an integral and cooperative role in this DC-dependent process by producing LT, which induces increased CXCL13 production by the LN stromal cells. Nematode infection–induced activation of the LT/CXCL13 positive-feedback loop facilitates the recruitment and retention of Ag-bearing, CXCR5-expressing DCs and CXCR5-expressing CD4 T cells near the B cell follicles. Localization of the DCs, T cells, and B cells in this LN microenvironment allows for exchange of cytokine and costimulatory signals among these three cell types and with other cells, such as the CXCL13-producing stromal cells that are present in this specialized niche. These location-dependent signals favor development of IL-4–producing TFH and Th2 cells and prevent the initiation of alternate effector fates.

FIGURE 1.

Cooperation between B cells and DCs can facilitate Th2 development in response to nematode infection. The accumulating data suggest that DCs are necessary, but not always sufficient, to initiate the priming of naive CD4 T cells and the initial commitment of the primed T cells to the Th2-developmental pathway. Ag-specific activated B cells can play an integral and cooperative role in this DC-dependent process by producing LT, which induces increased CXCL13 production by the LN stromal cells. Nematode infection–induced activation of the LT/CXCL13 positive-feedback loop facilitates the recruitment and retention of Ag-bearing, CXCR5-expressing DCs and CXCR5-expressing CD4 T cells near the B cell follicles. Localization of the DCs, T cells, and B cells in this LN microenvironment allows for exchange of cytokine and costimulatory signals among these three cell types and with other cells, such as the CXCL13-producing stromal cells that are present in this specialized niche. These location-dependent signals favor development of IL-4–producing TFH and Th2 cells and prevent the initiation of alternate effector fates.

Close modal

This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant R01 AI104725 (to F.E.L. and B.L.).

Abbreviations used in this article:

DAMP

damage-associated molecular pattern

DC

dendritic cell

HDM

house dust mite

LN

lymph node

LT

lymphotoxin α

MHCII

MHC class II

PAMP

pathogen-associated molecular pattern

PRR

pattern recognition receptor

TFH

T follicular helper

Treg

regulatory T cell.

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The authors have no financial conflicts of interest.