The development of IgE+ memory B cells following primary IgE immune responses

We studied whether long-lived IgE⁺ memory B cells develop following three types of primary IgE immune responses. Immunization of mice with anti-IgD antibody induced a T cell-dependent, interleukin (IL)-4-dependent primary IgE response and the formation of IgE isotype switched (IgE⁺) memory B cells. These IgE⁺ memory B cells could be stimulated in vivo by injection with goat anti-IgE antibodies to produce a profound IL-4-independent memory IgE response. By contrast, both infection of mice with Nippostrongylus brasiliensis or repeated immunization with benzylpenicilloyl-keyhole limpet hemocyanin (BPO-KLH) in alum stimulated good primary IgE responses and profound memory T cell-dependent antigen-specific IgE responses, but failed to induce the development of long lived IgE⁺ memory B cells because they could not be recalled with goat anti-IgE antibodies. Mice receiving double immunizations combining anti-IgD with either N. brasiliensis infection or BPO-KLH immunization mounted significant goat anti-IgE-induced secondary IgE responses, but no N. brasiliensis or BPO-KLH-specific IgE could be detected. This indicates that the N. brasiliensis and BPO-KLH induced immune responses do not suppress the development of IgE⁺ B cells, but rather, do not provide the necessary conditions for their formation. Taken together these data indicate that long-lived IgE⁺ B cells fail to develop during the primary IgE response to N. brasiliensis infection or BPO-KLH immunization. By contrast, significant numbers of IgE⁺ memory B cells form during the primary IgE immune response induced by anti-IgD immunization. Our observations suggest that immunization protocols involving membrane IgD cross-linking and limited duration of cognate T cell help are necessary for the formation of IgE⁺ memory B cells. It will be important to determine the relevance of membrane IgD interaction with allergens, as this would influence the design of new therapies for the treatment of allergy and asthma.     

Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus

Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory‐secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway response was suppressed, with ablated cell infiltration, a lower ratio of effector (CD4⁺CD25⁺Foxp3^?) to regulatory (CD4⁺Foxp3⁺) T (Treg) cells, and reduced Th1, Th2 and Th17 cytokine production. HES exposure reduced IL‐5 responses and eosinophilia, abolished IgE production and inhibited the type 2 innate molecules arginase‐1 and RELM‐α (resistin‐like molecule‐α). Although HES contains a TGF‐β‐like activity, similar effects in modulating allergy were not observed when administering mammalian TGF‐β alone. HES also protected previously sensitised mice, suppressing recruitment of eosinophils to the airways when given at challenge, but no change in Th or Treg cell populations was apparent. Because heat‐treatment of HES did not impair suppression at sensitisation, but compromised its ability to suppress at challenge, we propose that HES contains distinct heat‐stable and heat‐labile immunomodulatory molecules, which modulate pro‐allergic adaptive and innate cell populations.     

Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy

Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1–48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization.     

Induction of Th1 and Th2 CD4+ T cell responses by oral or parenteral immunization with ISCOMS

We examined the ability of oral or parenteral immunization with immune stimulating complexes containing ovalbumin (ISCOMS-OVA) to prime T cell proliferative and cytokine responses. A single subcutaneous immunization with ISCOMS-OVA primed potent antigen-specific proliferative responses in the draining popliteal lymph node, which were entirely dependent on the presence of CD4⁺ T cells. CD8⁺ T cells did not proliferate in vitro even in the presence of the appropriate peptide epitope and exogenous interleukin (IL)-2. Primed popliteal lymph node cells produced IL-2, IL-5 and interferon (IFN)-γ, but not IL-4 when restimulated with OVA in vitro. Serum antigen-specific IgG1 and IgG2a antibody responses were also primed by subcutaneous immunization with ISCOMS-OVA, confirming the stimulation of both Th1 and Th2 cells in vivo. Spleen cells from subcutaneously primed mice produced a similar pattern of cytokines, indicating that disseminated priming had occurred. Oral immunization with ISCOMS-OVA also primed local antigen-specific proliferative responses in the mesenteric lymph node and primed an identical pattern of systemic cytokine responses in the spleen. The ability of ISCOMS to prime both Th1 and Th2 CD4⁺ T cell responses may be central to their potent adjuvant activities and confirm the potential of ISCOMS as future oral vaccine vectors.     

Differentiation of distinct long-lived memory CD4 T cells in intestinal tissues after oral Listeria monocytogenes infection

Mucosal antigen-specific CD4 T-cell responses to intestinal pathogens remain incompletely understood. Here we examined the CD4 T-cell response after oral infection with an internalin A ‘murinized’ Listeria monocytogenes (Lm). Oral Lm infection induced a robust endogenous listeriolysin O (LLO)-specific CD4 T-cell response with distinct phenotypic and functional characteristics in the intestine. Circulating LLO-specific CD4 T cells transiently expressed the ‘gut-homing’ integrin α₄β₇ and accumulated in the intestinal lamina propria and epithelium where they were maintained independent of interleukin (IL)-15. The majority of intestinal LLO-specific CD4 T cells were CD27⁻ Ly6C⁻ and CD69⁺ CD103⁻ while the lymphoid LLO-specific CD4 T cells were heterogeneous based on CD27 and Ly6C expression and predominately CD69⁻. LLO-specific effector CD4 T cells transitioned into a long-lived memory population that phenotypically resembled their parent effectors and displayed hallmarks of residency. In addition, intestinal effector and memory CD4 T cells showed a predominant polyfunctional Th1 profile producing IFNγ, TNFα, and IL-2 at high levels with minimal but detectable levels of IL-17A. Depletion of CD4 T cells in immunized mice led to elevated bacterial burden after challenge infection highlighting a critical role for memory CD4 T cells in controlling intestinal intracellular pathogens.     

HIV-1 prophylactic vaccine comprised of topical DermaVir prime and protein boost elicits cellular immune responses and controls pathogenic R5 SHIV162P3

Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production and memory T cells. In rhesus macaques, DermaVir immunization induced Gag- and Env-specific Th1 and Th2 cytokines and generation of memory T cells. Boosting of DermaVir-primed serum antibody levels was noted following gp140(SHIV89.6P)/p27(SIV) immunization. Rectal challenge with pathogenic R5-tropic SHIV162P3 resulted in control of plasma viremia (4/5 animals) that was reflected in jejunum, colon and mesenteric lymph nodes. An inverse correlation was found between Gag- and Env-specific central memory T cell responses on the day of challenge and plasma viremia at set point. Overall, the topical DermaVir/protein vaccination yields central memory T cell responses and facilitates control of pathogenic SHIV infection.     

Parasite Proximity Drives the Expansion of Regulatory T Cells in Peyer's Patches following Intestinal Helminth Infection

Helminth infections are typically chronic in nature; however, the exact molecular mechanisms by which these parasites promote or thwart host immunity remain unclear. Worm expulsion requires the differentiation of CD4⁺ T cells into Th2 cells, while regulatory T cells (Tregs) act to dampen the extent of the Th2 response. Priming of T cells requires drainage or capture of antigens within lymphoid tissues, and in the case of intestinal helminths, such sites include the mucosa-associated Peyer''s patches (PPs) and the draining mesenteric lymph nodes (MLN). To gain insight into when and where the activation of the adaptive T cell response takes place following intestinal helminth infection, we analyzed Th2 and Treg responses in the PPs and MLN following infection with the murine intestinal helminth Heligmosomoides polygyrus bakeri. Protective Th2 responses were observed to be largely restricted to the MLN, while a greater expansion of Tregs occurred within the PPs. Interestingly, those PPs that formed a contact with the parasite showed the greatest degree of Treg expansion and no evidence of type 2 cytokine production, indicating that the parasite may secrete products that act in a local manner to selectively promote Treg expansion. This view was supported by the finding that H. polygyrus bakeri larvae could promote Treg proliferation in vitro. Taken together, these data indicate that different degrees of Treg expansion and type 2 cytokine production occur within the PPs and MLN following infection with the intestinal helminth H. polygyrus bakeri and indicate that these organs exhibit differential responses following infection with intestinal helminths.     

Anaplasma marginale infection with persistent high-load bacteremia induces a dysfunctional memory CD4+ T lymphocyte response but sustained high IgG titers

Control of blood-borne infections is dependent on antigen-specific effector and memory T cells and high-affinity IgG responses. In chronic infections characterized by a high antigen load, it has been shown that antigen-specific T and B cells are vulnerable to downregulation and apoptosis. Anaplasma marginale is a persistent infection of cattle characterized by acute and chronic high-load bacteremia. We previously showed that CD4(+) T cells primed by immunization with an A. marginale outer membrane protein were rapidly deleted following infection. Furthermore, peripheral blood T cell responses to bacteria were not observed after acute infection was controlled, suggesting dysfunctional T cell priming to other A. marginale antigens. The current study more closely investigated the kinetics of A. marginale-specific CD4(+) T cell responses primed during infection. Frequent sampling of peripheral blood and spleens revealed that antigen-specific CD4(+) T cell responses were first detected at 5 to 7 weeks, but the responses were sporadic and transient thereafter. A similar pattern was observed in animals sampled weekly for nearly 1 year. Paradoxically, by 2 weeks of infection, cattle had developed high titers of A. marginale-specific IgG, which remained high throughout persistent infection. This dysfunctional CD4(+) T cell response to infection is consistent with continual downregulation or deletion of newly primed effector T cells, similar to what was observed for immunization-induced T cells following A. marginale infection. The failure to establish a strong memory T cell response during A. marginale infection likely contributes to bacterial persistence.     

Plasmodium berghei sporozoite challenge of vaccinated BALB/c mice leads to the induction of humoral immunity and improved function of CD8+ memory T cells

Protection against malaria can be achieved by induction of a strong CD8⁺ T‐cell response against the Plasmodium circumsporozoite protein (CSP), but most subunit vaccines suffer from insufficient memory responses. In the present study, we analyzed the impact of postimmunization sporozoite challenge on the development of long‐lasting immunity. BALB/c mice were immunized by a heterologous prime/boost regimen against Plasmodium berghei CSP that induces a strong CD8⁺ T‐cell response and sterile protection, which is short‐lived. Here, we show that protective immunity is prolonged by a sporozoite challenge after immunization. Repeated challenges induced sporozoite‐specific antibodies that showed protective capacity. The numbers of CSP‐specific CD8⁺ T cells were not substantially enhanced by sporozoite infections; however, CSP‐specific memory CD8⁺ T cells of challenged mice displayed a higher cytotoxic activity than memory T cells of immunized‐only mice. CD4⁺ T cells contributed to protection as well; but CD8⁺ memory T cells were found to be the central mediator of sterile protection. Based on these data, we suggest that prolonged protective immunity observed after immunization and infection is composed of different antiparasitic mechanisms including CD8⁺ effector‐memory T cells with increased cytotoxic activity as well as CD4⁺ memory T cells and neutralizing antibodies.     

Airway T cells protect against RSV infection in the absence of antibody

Tissue resident memory T (Trm) cells act as sentinels and early responders to infection. Respiratory syncytial virus (RSV)-specific Trm cells have been detected in the lungs after human RSV infection, but whether they have a protective role is unknown. To dissect the protective function of Trm cells, BALB/c mice were infected with RSV; infected mice developed antigen-specific CD8⁺ Trm cells (CD103⁺/CD69⁺) in the lungs and airways. Intranasally transferring cells from the airways of previously infected animals to naïve animals reduced weight loss on infection in the recipient mice. Transfer of airway CD8 cells led to reduced disease and viral load and increased interferon-γ in the airways of recipient mice, while CD4 transfer reduced tumor necrosis factor-α in the airways. Because DNA vaccines induce a systemic T-cell response, we compared vaccination with infection for the effect of memory CD8 cells generated in different compartments. Intramuscular DNA immunization induced RSV-specific CD8 T cells, but they were immunopathogenic and not protective. Notably, there was a marked difference in the induction of Trm cells; infection but not immunization induced antigen-specific Trm cells in a range of tissues. These findings demonstrate a protective role for airway CD8 against RSV and support the need for vaccines to induce antigen-specific airway cells.     

Induction of a Th17 cell response by Helicobacter pylori Urease subunit B

Th17 cells represent a novel subset of CD4⁺ T cells, which is associated with Helicobacter pylori infection. In the present study, we investigated the potential role of Urease subunit B (UreB) in the induction of Th17 cell response. Co-cultured splenic lymphocytes from H. pylori-infected mice with the recombinant UreB (rUreB) elevated IL-17 secretion and caused an increase in the number of Th17 cells. The expression of IL-6 and IL-23 p19 was significantly increased in rUreB-stimulated macrophages. Whole cell protein (WCP) of UreB-deficient strain (UreB⁻ strain) induced less Th17 cell responses than that of wild-type strain. In addition, subcutaneous and intranasal immunization of rUreB elicited antigen-specific Th17 cell responses. Intranasal immunization of rUreB reduced H. pylori colonization in the stomach, which was closely related with the increased rUreB-specific Th17 cell responses. These results suggest that UreB is an important protein which is able to elicit Th17 cell responses against H. pylori both in vivo and in vitro.     

Intestinal helminth infection induces highly functional resident memory CD4+ T cells in mice

Immunity to intestinal nematodes requires CD4? Th2‐cell responses, including IL‐4 and IL‐13 production. Chronic infection with intestinal nematodes leads to downregulation of these responses, and few functional T helper (Th) 2 cells are detected in secondary lymphoid organs in the chronic phase or after abrogation of infection. Here, we show with a natural murine infection with Heligmosomoides polygyrus that highly functional memory Th2 cells persist in the lamina propria and in addition in the peritoneal cavity (PC) after abrogation of infection. While both tissue‐resident memory (T_RM) populations proliferate in situ and express IL‐4, IL‐5, and IL‐13 upon TCR‐dependent stimulation, only peritoneal memory cells express high levels of the IL‐33 receptor and produce IL‐5 and IL‐13 upon TCR‐independent stimulation with IL‐33 and IL‐7. Most importantly, PC‐derived T_RM cells are able to mediate anti‐helminthic effects by decreasing the fecundity of female worms upon transfer into recipient mice. These results show that nonlymphoid compartments can serve as reservoirs for Th2 memory cells, and furthermore that innate effector function of Th2 memory cells is restricted to CD4? memory T cells residing in the PC.     

Correction of antigen-specific T cell defects in aged murine gut-associated lymphoid tissues an immune intervention by combined adoptive transfer of an antigen-specific immunoregulatory CD4 T cell subset and interleukin 2 administration

Gut-associated lymphoid tissues (GALT) from aged mice enterically immunized with Mycobacterium paratuberculosis protoplasmic antigen show hyperreactive humoral immune responses; this hyperresponsiveness can be corrected to a considerable extent, but not entirely, by systemic administration of interleukin 2 (IL 2) alone. The aim of the present study was to determine further whether the hyperreactivity in the antigen-specific humoral immune responses in aged GALT could be fully restored by adoptive transfer of in vitro expanded antigen-specific IL 2-dependent helper (CD4⁺VV^?) T cells from GALT in conjunction with recombinant IL 2 administration. The results show that the age-associated hyperresponsiveness in gut mucosal antigen-specific humoral immune responses can be entirely corrected by adoptive transfer with the antigen-specific GALT T helper cells together with in vivo IL 2 adminstration. The mechanism of this restoration involves reversal of the decline in antigen-specific CD8⁺ suppressor T cell functions in aged GALT.     

Eosinophils are required to suppress Th2 responses in Peyer's patches during intestinal infection by nematodes

Infections with enteric nematodes result in systemic type 2 helper T (Th2) responses, expansion of immunoglobulin (Ig)G1 antibodies, and eosinophilia. Eosinophils have a supportive role in mucosal Th2 induction during airway hyperreactivity. Whether eosinophils affect the local T-cell and antibody response in the gut-associated lymphoid tissue during enteric infections is unknown. We infected eosinophil-deficient ΔdblGATA-1 mice with the Th2-inducing small intestinal nematode Heligmosomoides polygyrus and found that parasite fecundity was decreased in the absence of eosinophils. A lack of eosinophils resulted in significantly augmented expression of GATA-3 and IL-4 by CD4⁺ T cells during acute infection, a finding strictly limited to Peyer's patches (PP). The increase in IL-4-producing cells in ΔdblGATA-1 mice was particularly evident within the CXCR5⁺PD-1⁺ T-follicular helper cell population and was associated with a switch of germinal centre B cells to IgG1 production and elevated serum IgG1 levels. In contrast, infected wild-type mice had a modest IgG1 response in the PP, whereas successfully maintaining a population of IgA⁺ germinal center B cells. Our results suggest a novel role for eosinophils during intestinal infection whereby they restrict IL-4 responses by follicular T helper cells and IgG1 class switching in the PP to ensure maintenance of local IgA production.     

Immunization with adenovirus at the large intestinal mucosa as an effective vaccination strategy against sexually transmitted viral infection

The large intestinal mucosa contains immunological structures that may potentially serve as a site for induction of mucosal immunity against infections. Adenovirus (Ad), which is effective in gene transfer to epithelia, may be an ideal antigen delivery system for vaccination at the large intestinal mucosa. To investigate this potential, we immunized mice with recombinant replication-deficient Ad through a single intracolorectal (ICR) administration. Effective transfer of encoded genes was found in both the epithelial layer and lamina propria of the colorectal mucosa. Dendritic cells were able to transfer antigen to the draining lymph nodes, where antigen-specific CD8⁺ T cells were primed. Functional antigen-specific CD8⁺ T cells and IgA-specific antibodies were detected during the effector phase in the large intestine. Compared to other immunization routes (intranasal, subcutaneous), ICR immunization induced stronger colorectal immune responses and more potent protection against rectal challenge with pathogenic viruses. Further, this immunization strategy provided vaginal protection, more potent than that induced by vaccination in the nose or skin. Therefore, large intestine mucosal immunization using Ad represents an effective vaccination strategy against virus infection at both rectal and vaginal mucosal tissue sites.     

Intrinsic 4-1BB signals are indispensable for the establishment of an influenza-specific tissue-resident memory CD8 T-cell population in the lung

The induction of long-lived heterotypic T-cell protection against influenza virus remains elusive, despite the conservation of T-cell epitopes. T-cell protection against influenza is critically dependent on lung-resident memory T cells (Trm). Here we show that intranasal administration of 4-1BBL along with influenza nucleoprotein in a replication-defective adenovirus vector to influenza pre-immune mice induces a remarkably stable circulating effector memory CD8 T-cell population characterized by higher IL-7Rα expression than control-boosted T cells, as well as a substantial lung parenchymal CD69⁺ CD8 Trm population, including both CD103⁺ and CD103⁻ cells. These T-cell responses persist to greater than 200 days post-boost and protect against lethal influenza challenge in aged (year old) mice. The expansion of the nucleoprotein-specific CD8 Trm population during boosting involves recruitment of circulating antigen-specific cells and is critically dependent on local rather than systemic administration of 4-1BBL as well as on 4-1BB on the CD8 T cells. Moreover, during primary influenza infection of mixed bone marrow chimeras, 4-1BB-deficient T cells fail to contribute to the lung-resident Trm population. These findings establish both endogenous and supraphysiological 4-1BBL as a critical regulator of lung-resident memory CD8 T cells during influenza infection.     

Cell cooperation during in vivo anti-hapten antibody responses: V. Two synergistic Ly-1+23− helper T cells with distinctive specificities

Experiments were carried out to determine the antigen specificity of two distinct helper T cells (Th) that act synergistically in adoptive secondary in vivo anti-hapten antibody responses. Both Th were present in anti-Ly-2 and complement-treated spleen T cell populations, implying that both Th are Ly-1⁺,23^?. Adding normal T cells or T cells primed to other carriers to specific carrier-primed T cells, using a variety of different protocols did not affect the helper activity of the specifically primed Th. Thus, both Th apparently are antigen-specific. Furthermore, Th primed with one carrier and boosted with that carrier plus hapten linked to a noncross- reactive carrier cannot help B cells. However, if a mixture of Ly-1 T cells from mice primed with two different carriers is transferred along with B cells, and the mice are boosted with hapten coupled to one of the two priming carriers, then giving the other carrier induces a significant increase in antibody production. Thus, only one of the two Th (Th1) requires a hapten-carrier bridge, while the other does not (Th2). However, both Th 1 and Th2 are clearly antigen-specific and require stimulation with antigen to exert helper activity. Furthermore, these experiments strongly suggest that Th 2 cannot express helper function in vivo in the absence of Th 1. These findings, and the absence of Th2-like cells in agammaglobulinemic mice, were correlated with other studies in which two helper activities have been described. It was concluded that in vivo responses require an effective Th 1-B cell interaction, whereas Th2, if stimulated with antigen, will augment certain portions of the antibody response, such as idiotype or allotype, and thus influence the quality of the antibody response directly.     

Signal 3 requirement for memory CD8+ T-cell activation is determined by the infectious pathogen

The relevance of direct inflammatory signals (signal 3) for the activation of memory CD8⁺ T cells during recall responses is so far unknown. We therefore investigated the direct impact of IL‐12 and type I IFN on the formation, recall potential and protective capacity of memory T cells. Using CD8⁺ T cells deficient for IL‐12 or type I IFN receptors in an adoptive transfer system, we generated memory populations after infection with vaccinia virus, lymphocytic choriomeningitis virus or Listeria monocytogenes. The results demonstrate that in the absence of signal 3 cytokines during primary infection, functional memory T cells were formed. After retransfer into naïve mice, signal 3‐deficient memory T cells were able to specifically lyse target cells in vivo under non‐infectious conditions. However, after reinfection, secondary effector CD8⁺ T cells lacking signal 3 were impaired in expansion and protective capacity dependent on the nature of the pathogen. We conclude that memory CD8⁺ T cells depend on a signal 3 for expansion, independent of signals obtained during priming, thereby being influenced by the pathogen‐induced inflammatory milieu during secondary infection. In summary, our results reveal an essential role for direct inflammatory cytokine signaling in secondary T‐cell responses.     

IL‐6 controls susceptibility to helminth infection by impeding Th2 responsiveness and altering the Treg phenotype in vivo

IL‐6 plays a pivotal role in favoring T‐cell commitment toward a Th17 cell rather than Treg‐cell phenotype, as established through in vitro model systems. We predicted that in the absence of IL‐6, mice infected with the gastrointestinal helminth Heligmosomoides polygyrus would show reduced Th17‐cell responses, but also enhanced Treg‐cell activity and consequently greater susceptibility. Surprisingly, worm expulsion was markedly potentiated in IL‐6‐deficient mice, with significantly stronger adaptive Th2 responses in both IL‐6^?/? mice and BALB/c recipients of neutralizing anti‐IL‐6 monoclonal Ab. Although IL‐6‐deficient mice showed lower steady‐state Th17‐cell levels, IL‐6‐independent Th17‐cell responses occurred during in vivo infection. We excluded the Th17 response as a factor in protection, as Ab neutralization did not modify immunity to H. polygyrus infection in BALB/c mice. Resistance did correlate with significant changes to the associated Treg‐cell phenotype however, as IL‐6‐deficient mice displayed reduced expression of Foxp3, Helios, and GATA‐3, and enhanced production of cytokines within the Treg‐cell population. Administration of an anti‐IL‐2:IL‐2 complex boosted Treg‐cell proportions in vivo, reduced adaptive Th2 responses to WT levels, and fully restored susceptibility to H. polygyrus in IL‐6‐deficient mice. Thus, in vivo, IL‐6 limits the Th2 response, modifies the Treg‐cell phenotype, and promotes host susceptibility following helminth infection.