Th1 Development Research Articles

IL-27 and IL-35 as gene therapy of neuroinflammation

Interleukin 27 and 35 belong to IL-12 cytokine family, which also includes, IL-12, IL-23. Even if all cytokines, belonging to this family, present a structural homology, they mediate different functions. In particular, IL-12 and IL-23 are mostly pro-inflammatory cytokines, with, respectively, key roles in the development of TH1 and TH17 cells, which represent the crucial effector cells in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). IL-27 and IL-35 are mainly immunomodulatory cytokines and principally act on immune cell-mediated response.

Abstract 4074: Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation

Abstract It is recently reported that CD40-CD40 ligand (CD40L) interaction is important to Th17 development. Also, it is known that transforming growth factor-beta (TGF-β) promotes tumorigenesis as an immunosuppressive cytokine and is crucial for the development of Th17. In this study, we investigated the role of CD40 on breast cancer cells and its role on the immune suppressive function and tumor progression. CD40 stimulation on breast cancer cell line, MDA-MB231, caused up-regulation of TGF-β, and direct CD40-CD40L interaction between breast cancer cells and activated T cells increased TFG-β production. Moreover, direct interaction of CD40-CD40L induced the production of IL-17, which increased the proliferation of MDA-MB231 cells via the activation of STAT3. Therefore, direct CD40-CD40L interaction of breast tumor and activated T cells increases the TGF-β production and the differentiation of Th17 cells, which promote the proliferation of breast cancer cells. Citation Format: Hyemin Kim, Yejin Kim, Jiwon Choi, Mirim Jang, Jiyea Choi, Young-il Hwang, Jae Seung Kang, Wang Jae Lee. Direct interaction of CD40 on tumor cell with CD40L on T cells increases the proliferation of tumor cells via the enhancement of TGF-b production and Th17 differentiation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4074. doi:10.1158/1538-7445.AM2014-4074

Suppression of human and mouse Th17 differentiation and autoimmunity by an endogenous Interleukin 23 receptor cytokine-binding homology region

T-helper 17 (Th17) cells, a recently identified CD4+ T subset with a unique characteristic to produce Interleukin-17 (IL-17), are critical for the development of autoimmune diseases such as multiple sclerosis, in which IL-23 plays an important role in the differentiation of Th17 cells through IL-23/IL-23-receptor/STAT3 pathway. Previously, soluble recombinant human IL-23 receptor cytokine-binding homology region (hIL23R-CHR) was constructed in our laboratory to neutralize IL-23 and inhibit murine Th17 development in vitro. Herein we present that hIL23R-CHR could inhibit both differentiation and function of human/murine Th17 cells. The present in vivo study further demonstrated that hIL23R-CHR inhibited murine Th17 cell development by down regulating IL-17 gene expression and protected mice against the development of experimental autoimmune encephalomyelitis (EAE) through suppression of CNS inflammation and pro-inflammatory cytokine production. In addition to the in vitro inhibition of human Th17 cells in a dose-dependent manner, the antagonizing effect of hIL23R-CHR was confirmed by reduced levels of IL-23 in both blood and brain of EAE mice and STAT3 phosphorylation in vivo. Taken together, our data demonstrated that hIL23R-CHR could be an effective and specific immunosuppressive molecule for the treatment of Th17-related autoimmune diseases.

Ebf3-miR218 regulation is involved in the development of dopaminergic neurons

The development of midbrain dopaminergic (DA) neurons is a complex process that requires the precise spatial and temporal expression of numerous genes. Here, we report that Ebf3, a transcription factor, plays a critical role in the terminal development of DA neurons. We found a specific upregulation of Ebf3 in Dicer knockout midbrain DA neurons and dynamic patterns of Ebf3 expression during the development of DA neurons. We further demonstrated that the overexpression of Ebf3 at the neural precursor stage of embryonic stem (ES) differentiation induces a significant increase in the number of TH+ DA neurons, whereas the suppression of Ebf3 leads to significant reduction in the development of TH+ DA neurons. Additionally, we found that Ebf3 is a candidate target for miR218 during DA neuronal development, such that the regulation of Ebf3 expression by miR218 controls the terminal differentiation of DA neurons. Thus, our data suggest that complex transcription factor–miRNA regulation is critical for the development of midbrain DA neurons.

Grail controls Th2 cell development by targeting STAT6 for degradation.

T helper (Th)-2 cells are the major players in allergic asthma; however, the mechanisms that control Th2-mediated inflammation are poorly understood. Here we find that enhanced expression of Grail, an E3 ubiquitin ligase, in Th2 cells depends on IL-4-signaling components, Stat6 and Gata3 that bind to and transactivate the Grail promoter. Grail-deficiency in T cells leads to increased expression of Th2 effector cytokines in vitro and in vivo and Grail deficient mice are more susceptible to allergic asthma. Mechanistically, the enhanced effector function of Grail-deficient Th2 cells is mediated by increased expression of Stat6 and IL-4 receptor α-chain. Grail interacts with Stat6 and targets it for ubiquitination and degradation. Thus, our results indicate that Grail plays a critical role in controlling Th2 development through a negative feedback loop.

Dendritic Cells and B Cells: Unexpected Partners in Th2 Development

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.

Studies on recombinant glucokinase (r-glk) protein of Brucella abortus as a candidate vaccine molecule for brucellosis

Brucellosis is one of the most prevalent zoonotic diseases of worldwide distribution caused by the infection of genus Brucella. Live attenuated vaccines such as B. abortus S19, B. abortus RB51 and B. melitensis Rev1 are found most effective against brucellosis infection in animals, contriving a number of serious side effects and having chances to revert back into their active pathogenic form. In order to engineer a safe and effective vaccine candidate to be used in both animals and human, a recombinant subunit vaccine molecule comprising the truncated region of glucokinase (r-glk) gene from B. abortus S19 was cloned and expressed in Escherichia coli BL21DE3 host. Female BALB/c mice immunized with purified recombinant protein developed specific antibody titer of 1:64,000. The predominant IgG2a and IgG2b isotypes signified development of Th1 directed immune responses. In vitro cell cytotoxicity assay using anti-r-glk antibodies incubated with HeLa cells showed 81.20% and 78.5% cell viability against lethal challenge of B. abortus 544 and B. melitensis 16M, respectively. The lymphocyte proliferative assay indicated a higher splenic lymphocyte responses at 25μg/ml concentration of protein which implies the elevated development of memory immune responses. In contrast to control, the immunized group of mice intra-peritoneal (I.P.) challenged with B. abortus 544 were significantly protected with no signs of necrosis and vacuolization in their liver and spleen tissue. The elevated B-cell response associated with Th1 adopted immunity, significant in vitro cell viability as well as protection afforded in experimental animals after challenge, supplemented with histopathological analysis are suggestive of r-glk protein as a prospective candidate vaccine molecule against brucellosis.

Immunomodulatory properties of green propolis.

Propolis is a resinous material collected by honeybees from numerous plants and serves as a defense against intruders. Because of its relevant curative properties, it is now gaining popularity in health foods and in cosmetic products. Understanding the underlying molecular mechanisms of phytochemicals has become a good strategy in bioprospection for new anti-inflammatory compounds. The biological activity of propolis derives from its high levels of phenolic acids, while flavonoids are thought to account for the activity of propolis extracts. The comprehension of the relationship between propolis and the immune system has progressed in the last years, recent articles have provided important contributions to this investigation field. Studies have shown that propolis suppressed the "IL-6-induced phosphorylation of signal transducer and STAT3", an essential cytokine-activated transcription factor in Th17 development. Therefore, action mechanisms of "propolis on Th17 differentiation could be instrumental in controlling disturbed cytokine networks in inflammation, autoimmune diseases, and infections." The use of propolis has been proposed in some patents as: WO201363714; CN102885854, WO2013142936, US20130266521, and US20130129808, which are related to the treatment of dental diseases; adjuvant in anti-cancer treatment; in cosmetic products; as an anti-inflammatory agent and natural antibiotic. Although there are many publications regarding the propolis efficacy, its applicability to human health and mechanisms of action are not completely understood, creating opportunities for new studies.

Carbon monoxide-releasing molecule-A1 inhibits Th1/Th17 and stimulates Th2 differentiation in vitro.

Carbon monoxide (CO) is endogenously produced by haeme oxygenase-1 and has profound effects on intracellular signalling processes, generating anti-inflammatory, antiproliferative and antiapoptotic effects. A boron-containing compound CORM-A1 is capable of releasing CO in such a way to mimic physiological functions of haeme oxygenase-1. Considering the importance of Th1/Th17 versus Th2 balance in the final outcome of immune and inflammatory responses in this study we focused on immune-modulatory effects of CORM-A1 on murine lymph node-derived T cells in vitro and its influence on T-cell proliferation, activation and differentiation. Anti-CD3/CD28 antibody-triggered lymph node cells proliferation remained unaffected after 24-hour CORM-A1 treatment, as well as the expression of the early activation marker CD25. However, CORM-A1 successfully reduced the secretion of the two representative pro-inflammatory cytokines, IFN-γ and IL-17, while the secretion of anti-inflammatory cytokine IL-4 remained unchanged. Furthermore, CORM-A1 efficiently reduced the percentage of CD4(+) IFN-γ(+) and CD4(+) IL-17(+) cells, whereas CD4(+) IL-4(+) cell population increased after treatment. Also, CORM-A1 significantly reduced expression of transcription factor RORγT, necessary for Th17 development, but the expression of Th1-related and Th2-related transcription factors (T-bet and GATA-3, respectively) remained unchanged. In conclusion, our findings indicate that CO has anti-inflammatory role through the regulation of balance between pro-inflammatory Th1/Th17 and anti-inflammatory Th2 cells. Observed immunomodulatory effects of CORM-A1 could be useful for developing novel therapeutic approaches in managing Th1/Th17-mediated immune disorders.

MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis

Unlike genetic alterations, epigenetic modifications are reversible and amenable to pharmacological interventions, which make them appealing targets for clinical therapy. However, little is known about epigenetic regulation in experimental autoimmune encephalomyelitis (EAE). Here we demonstrated that methyl-CpG-binding domain protein 2 (MBD2), an epigenetic regulator, controls autoimmunity and EAE through T-bet/Hlx. Tbx21 and Hlx underwent a DNA methylation turnover upon polarizations and a unique methylation pattern was essential for TH17 development. Loss of Mbd2 resulted in a defect for reading the information encoded by this methylation turnover, which disrupted the homeostasis of T-bet/Hlx axis and suppressed TH17 differentiation. DNA demethylation induced similar effect on helper T cell differentiation. Therefore, Mbd2−/− mice were completely protected from EAE. Pathogenic splenocytes isolated from wild-type mice challenged with MOG35-55 could adoptively transfer disease to Mbd2−/− mice. In addition, Mbd2−/− mice reconstituted with unstimulated wild-type splenocytes developed EAE as wild-type mice did. These data would provide novel insights into epigenetic regulation of EAE.

STAT4 deficiency fails to induce lung Th2 or Th17 immunity following primary or secondary respiratory syncytial virus (RSV) challenge but enhances the lung RSV-specific CD8+ T cell immune response to secondary challenge.

Immune-mediated lung injury is a hallmark of lower respiratory tract illness caused by respiratory syncytial virus (RSV). STAT4 plays a critical role in CD4+ Th1 lineage differentiation and gamma interferon (IFN-γ) protein expression by CD4+ T cells. As CD4+ Th1 differentiation is associated with negative regulation of CD4+ Th2 and Th17 differentiation, we hypothesized that RSV infection of STAT4-/- mice would result in enhanced lung Th2 and Th17 inflammation and impaired lung Th1 inflammation compared to wild-type (WT) mice. We performed primary and secondary RSV challenges in WT and STAT4-/- mice and used STAT1-/- mice as a positive control for the development of RSV-specific lung Th2 and Th17 inflammation during primary challenge. Primary RSV challenge of STAT4-/- mice resulted in decreased T-bet and IFN-γ expression levels in CD4+ T cells compared to those of WT mice. Lung Th2 and Th17 inflammation did not develop in primary RSV-challenged STAT4-/- mice. Decreased IFN-γ expression by NK cells, CD4+ T cells, and CD8+ T cells was associated with attenuated weight loss and enhanced viral clearance with primary challenge in STAT4-/- mice compared to WT mice. Following secondary challenge, WT and STAT4-/- mice also did not develop lung Th2 or Th17 inflammation. In contrast to primary challenge, secondary RSV challenge of STAT4-/- mice resulted in enhanced weight loss, an increased lung IFN-γ expression level, and an increased lung RSV-specific CD8+ T cell response compared to those of WT mice. These data demonstrate that STAT4 regulates the RSV-specific CD8+ T cell response to secondary infection but does not independently regulate lung Th2 or Th17 immune responses to RSV challenge. STAT4 is a protein critical for both innate and adaptive immune responses to viral infection. Our results show that STAT4 regulates the immune response to primary and secondary challenge with RSV but does not restrain RSV-induced lung Th2 or Th17 immune responses. These findings suggest that STAT4 expression may influence lung immunity and severity of illness following primary and secondary RSV infections.

HCV infection enhances Th17 commitment, which could affect the pathogenesis of autoimmune diseases.

BackgroundVarious kinds of autoimmune diseases have been reported to have a significant relationship with persistent hepatitis c virus (HCV) infection and Th17 cells. Previously, our group reported that the existence of HCV in T lymphocytes could affect the development of CD4+ helper T cells and their proliferation, in addition to the induction of immunoglobulin hyper-mutation.MethodsTherefore, we analyzed the relationship between persistent infection of HCV and the mechanism of Th17 cell induction ex vivo and in vitro.ResultsThe prevalence of autoimmune-related diseases in chronic hepatitis c patients (CH-C) was significantly higher than in other types of chronic hepatitis (hepatitis B and NASH). A significantly higher frequency of IL6 and TGF-β double-high patients was detected in CH-C than in other liver diseases. Moreover, these double-high patients had significantly higher positivity of anti-nuclear antibody, cryoglobulinemia, and lymphotropic HCV and higher amounts of IL1-β, IL21, IL23. In addition to the previously reported lymphotropic SB-HCV strain, we found a novel, genotype 1b lymphotropic HCV (Ly-HCV), by deep sequencing analysis. Lymphotropic-HCV replication could be detected in the lymphoid cells with various kinds of cytokine-conditions including IL1β, IL23, IL6 and TGF-β in vitro. Infection by HCV could significantly enhance the development of Th17 cells. The HCV protein responsible for inducing the Th17 cells was HCV-Core protein, which could enhance the STAT-3 signaling and up-regulate the expression of RORγt as a Th17 master gene.ConclusionInfection by lymphotropic HCV might enhance the Th17 development and contribute to understanding the pathogenesis of autoimmune-related diseases.

OP0223 Increased TH17 Cell Frequency and Poor Clinical Outcome in Rheumatoid Arthritis Are Associated with A Genetic Variant in the IL-4R Gene, Rs1805010

BackgroundThe minor allele of the interleukin-4 receptor (IL4R) gene single nucleotide polymorphism (SNP), I50V (rs1805010), confers impaired IL-4 signaling and has been associated with an aggressive destructive course of rheumatoid...

The role of basophils and proallergic cytokines, TSLP and IL-33, in cutaneously sensitized food allergy

Cutaneous sensitization with a food antigen before its consumption elicits the development of food allergy. Here, we report the site- and stage-dependent roles of basophils and proallergic cytokines, thymic stromal lymphopoietin (TSLP) and IL-33, in a mouse model of food allergy initially sensitized cutaneously with the food antigen. Mice were epicutaneously sensitized with the food antigen ovalbumin (OVA) followed by oral challenge with OVA. Epicutaneously sensitized mice produced OVA-specific IgE and developed IgE-dependent anaphylaxis after oral challenge. Basophil-depleted or TSLP-receptor-deficient mice did not produce OVA-specific IgE and were protected from oral challenge-induced anaphylaxis. IL-33-deficient mice produced normal levels of OVA-specific IgE. However, IL-33-deficient mice and mice treated with recombinant soluble IL-33 receptor were protected from anaphylaxis. Thus, basophils and TSLP have pivotal roles in Th2 development in the skin during the sensitization phase of food allergy. In contrast, while IL-33 is dispensable for promoting cutaneous antigen sensitization, the cytokine is essential for inducing IgE-dependent anaphylaxis in the gut.

Serine protease inhibition attenuates rIL-12-induced GZMA activity and proinflammatory events by modulating the Th2 profile from estrogen-treated mice.

Estrogen has potent immunomodulatory effects on proinflammatory responses, which can be mediated by serine proteases. We now demonstrate that estrogen increased the extracellular expression and IL-12-induced activity of a critical member of serine protease family Granzyme A, which has been shown to possess a novel inflammatory persona. The inhibition of serine protease activity with inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride significantly diminished enhanced production of proinflammatory interferon-γ, IL-1β, IL-1α, and Granzyme A activity even in the presence of a Th1-inducing cytokine, IL-12 from splenocytes from in vivo estrogen-treated mice. Inhibition of serine protease activity selectively promoted secretion of Th2-specific IL-4, nuclear phosphorylated STAT6A, signal transducer and activator of transcription (STAT)6A translocation, and STAT6A DNA binding in IL-12-stimulated splenocytes from estrogen-treated mice. Inhibition with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride reversed the down-regulation of Th2 transcription factors, GATA3 and c-Maf in splenocytes from estrogen-exposed mice. Although serine protease inactivation enhanced the expression of Th2-polarizing factors, it did not reverse estrogen-modulated decrease of phosphorylated STAT5, a key factor in Th2 development. Collectively, data suggest that serine protease inactivity augments the skew toward a Th2-like profile while down-regulating IL-12-induced proinflammatory Th1 biomolecules upon in vivo estrogen exposure, which implies serine proteases as potential regulators of inflammation. Thus, these studies may provide a potential mechanism underlying the immunomodulatory effect of estrogen and insight into new therapeutic strategies for proinflammatory and female-predominant autoimmune diseases.

TLR-CD40 Cross-Talk in Anti-Leishmanial Immune Response.

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and activate innate immune cells to induce cytokines and co-stimulatory molecules such as CD40 and to enhance antigen presentation to T cells (1) that, upon activation, can either eliminate or support the pathogen (2). Herein, we propose that this duality in TLR functions results from their cross-talk with CD40. While all TLRs enhance CD40 expression, CD40 augments the expression of only TLR9 (3). As both CD40 and TLR9 induce expression of IL-12, a cytokine that induces the IFN-γ secreting Th1 cell differentiation (4), the CD40–TLR9 cross-regulation implies a positive feedback loop. By contrast, TLR1–TLR2 heterodimer down-regulates TLR9 expression (5) and antagonizes the development of Th1 response but favors the differentiation of regulatory T (T-reg) cells (Pandey et al., unpublished observation). Low CD40 expression levels in dendritic cells also promote T-reg cell differentiation (6). This duality can emerge from the sharing of signaling molecules. CD40 induces TRAF6-mediated, ERK-1/2-dependent IL-10 (7), which can inhibit the TLR-induced p38-MAPK activation and IL-12 production, antagonizing Th1 development. CD40-induced TRAF3-dependent p38-MAPK activation (7) can synergize with the TLR-activated p38-MAPK-dependent IL-12 production and Th1 differentiation. Using Leishmania infection, we show that the TLR–CD40 cross-talk can induce contrasting anti-leishmanial immune responses. Leishmania, a protozoan parasite, lives in macrophages. Leishmania expresses lipophosphoglycan (LPG), proteoglycans, flagellin, and profilin for possible recognition by the host cell-expressed TLRs. Recognition of the Leishmania-expressed PAMPs results in differential immune responses, which can either reduce or exacerbate Leishmania infection. As TLRs modulate the expression of CD40, a co-stimulatory molecule whose expression levels modulate anti-leishmanial T cell responses, we propose that TLR–CD40 cross-talk significantly regulate the outcome of an anti-leishmanial immune response.

Type I interferon suppresses de novo virus-specific CD4 Th1 immunity during an established persistent viral infection.

CD4 T cells are central to orchestrate, sustain, and potentially regenerate antiviral immunity throughout persistent viral infections. Although the evolving immune environment during persistent infection reshapes established CD4 T-cell responses, the fate of naïve CD4 T cells primed in the midst of persistent infection is unclear. We demonstrate that, in marked contrast to the onset of infection, virus-specific CD4 T cells primed during an established persistent infection have diminished ability to develop Th1 responses, to efficiently accumulate in peripheral tissues, and almost exclusively differentiate into T follicular helper cells. Consistent with suppressed Th1 and heightened Tfh differentiation, virus-specific CD4 T cells primed during the established persistent infection provide help to B cells, but only limited help to CD8 T cells. The suppression of de novo Th1 generation and tissue distribution was mediated by chronic type I IFN (IFN-I) production and was effectively restored by blocking IFN-I signaling during CD4 T-cell priming. Thus, we establish a suppressive function of chronic IFN-I signaling and mechanism of immunoregulation during an established persistent virus infection.

BATF dependency of Th9-associated genes (HYP7P.290)

Abstract Th9 cells are a recently described T helper subset that develops in the presence of TGF-β and IL-4. Th9 cells promote allergic inflammation, anti-tumor immunity, and may contribute to the regulation of auto inflammatory disease. Th9 cells are specialized for IL-9 production and this requires transcription factors including STAT6, PU.1 and IRF4. We have recently described that BATF promotes Th9 development in both mouse and human cells and BATF is required for T cells to promote the development of allergic inflammation. BATF-transduced Th9 cells demonstrated a potent ability to promote allergic inflammation in vivo compared to control transduced Th9 cells. To begin to define the transcriptional network controlling genes in Th9 cells, we characterized the dependence of Th9-enriched genes on each transcription factor, including BATF. Multiple genes including transcription factors, cytokines, and cytokine receptors were BATF-dependent. Unique functional properties of Th9 cells are suggested by the Th9-enriched expression of IL-33R, IL-25R, granzyme A, ephrin A5, and the salt-sensitive serum glucocorticoid kinase. BATF is required for 14/19 genes studied in detail thus far, suggesting that it is a major controller of the Th9 genetic program. Further defining of the module of BATF-dependent genes will aid in integrating the circuitry of Th9 development and function.

T helper 9 (Th9) cellular proliferation and cytokine production is regulated by cAMP responsive element modulator (Crem) (HYP7P.289)

Abstract Th9 cells, a CD4+ T cell subset characterized by their robust production of interleukin (IL)-9, can promote allergic inflammation in mice and are associated with atopic disease in humans. Because it might provide targets for therapeutic intervention, it is important to understand the molecular controls governing overall Th9 development and their subsequent effector function. To understand the Th9 transcriptional profile, we recently performed microarray analysis to highlight gene expression enriched in Th9 cells compared to other Th subsets. Crem, which expresses a basic leucine zip domain protein with roles in activating and repressing genes, was among a number of genes with increased expression in Th9 cells. Analysis of mRNA and protein expression among in vitro differentiated Th subsets confirmed Crem was enriched in Th9 cells compared to other subsets. Interestingly, ectopic expression of Crem in Th9 cells repressed their capacity to produce IL-9 upon CD3 re-stimulation while promoting overall cellular proliferation. Crem ectopic expression also promoted cellular expansion in other cultured Th subsets. Conversely, acute siRNA knockdown of Crem mRNA in Th9 differentiated cells resulted in reduced cellular proliferation and enhanced IL-9 production upon CD3 restimulation. Therefore, Crem potentially serves a role in modifying Th9 effector activities upon T cell receptor signaling during allergic disease.

Basic leucine zipper transcription factor, ATF-like (BATF) is essential for the development of protective immunity against parasitic helminth infection (MPF1P.779)

Abstract Parasitic helminth infections afflict roughly a quarter of the world’s population. Immunity against parasitic helminth infection relies on the induction of allergic inflammation. Major hallmarks of allergic inflammation, such as IgE, eosinophilia, and mucus production, depend on the cytokines interleukin-4 (IL-4) and IL-13. In mice, IL-4 from CD4+ follicular T helper (Tfh) cells is required for IgE production, while IL-13 from CD4+ T-helper 2 (Th2) cells is required for worm clearance and mucus production. The basic leucine zipper transcription factor, ATF-like (BATF) is critical for Tfh function, however its necessity in Th2 cell development and IL-4 production remains unclear. To investigate the role of BATF in the context of allergic inflammation, we infected wild-type and BATF-deficient mice with the helminth Nippostrongylus brasiliensis to compare the resultant immune responses. In wild-type mice, N. brasiliensis infection induced a robust response as indicated by lung eosinophilia, high serum IgE, and worm expulsion. In contrast, BATF-deficient mice exhibited dramatically reduced eosinophilia, no IgE, and were unable to clear parasites from the intestine. Studies with IL-4-reporter mice revealed that these defects in allergic immunity were attributed to impaired Tfh and Th2 cell development. These findings suggest that BATF plays a central role in protection against helminths, and BATF is critical for the development of both Th2 and Tfh cells during allergic responses.